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Sample records for dual renin-angiotensin system

  1. Intratubular Renin-Angiotensin System in Hypertension

    PubMed Central

    Suzaki, Yuki; Prieto-Carrasquero, Minolfa C.; Kobori, Hiroyuki

    2009-01-01

    It is well recognized that the renin-angiotensin system plays an important role in the regulation of arterial pressure and sodium homeostasis. Recent years, many studies have shown that local tissue angiotensin II levels are differentially regulated and cannot be explained on the basis of circulating concentrations. All of the components needed for angiotensin II generation are present within the various compartments in the kidney including the renal interstitium and the tubular network. The cascade of the renin-angiotensin system demonstrates three major possible sites for the pharmacological interruption of the renin-angiotensin system: the interaction of renin with its substrate, angiotensinogen, the angiotensin converting enzyme, and angiotensin II type 1 receptors. This brief article will focus on the role of the intratubular renin-angiotensin system in the pathophysiology of hypertension and the responses to the renin-angiotensin system blockade by renin inhibitors, angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockers. PMID:19789728

  2. Reproduction and the renin-angiotensin system

    NASA Technical Reports Server (NTRS)

    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.

  3. Reproduction and the renin-angiotensin system.

    PubMed

    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.

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

    PubMed

    Werner, Christian; Pöss, Janine; Böhm, Michael

    2010-07-01

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

  5. The Renal Renin-Angiotensin System

    ERIC Educational Resources Information Center

    Harrison-Bernard, Lisa M.

    2009-01-01

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

  6. Potassium Handling with Dual Renin-Angiotensin System Inhibition in Diabetic Nephropathy

    PubMed Central

    Adams-Huet, Beverley; Nguyen, Mark; Molina, Christopher; Toto, Robert D.

    2014-01-01

    Summary Background and objectives Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the cornerstones of pharmacologic therapy in diabetic nephropathy. Mineralocorticoid receptor blockers reduce proteinuria as single agents or add-on therapy to other renin-angiotensin-aldosterone system-inhibiting drugs in these patients. The long-term benefits and ultimate role of mineralocorticoid receptor blockers in diabetic nephropathy remain unknown. A clinical trial previously showed that the kalemic effect of spironolactone is higher than losartan when added to lisinopril in patients with diabetic nephropathy. The purpose of this study was to investigate if renal potassium handling was primarily responsible for that observation. Design, setting, participants, & measurements In a blinded, randomized, three-arm placebo-controlled clinical trial, 80 participants with diabetic nephropathy taking lisinopril (80 mg) were randomized to spironolactone (25 mg daily), losartan (100 mg daily), or placebo (trial dates from July of 2003 to December of 2006). Serum potassium, aldosterone, and 24-hour urine sodium, potassium, and creatinine were measured over 48 weeks. Differences were analyzed with repeated measures mixed models. Results Mean follow-up serum potassium was 5.0 mEq/L for spironolactone, 4.7 mEq/L for losartan (P=0.05 versus spironolactone), and 4.5 mEq/L for placebo (P<0.001 versus spironolactone; P=0.03 versus losartan). The difference in serum potassium was 0.23 mEq/L for losartan versus placebo (P=0.02), 0.43 mEq/L for spironolactone versus placebo (P<0.001), and 0.2 mEq/L for spironolactone versus losartan (P=0.05). Serum and urine potassium excretion and secretion rates were similar between groups throughout the study. Conclusion Spironolactone raised serum potassium more than losartan in patients with diabetic nephropathy receiving lisinopril, despite similar renal sodium and potassium excretion. This finding suggests that extrarenal

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

    PubMed

    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.

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

    PubMed Central

    Plotkin, Horacio

    2016-01-01

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

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

    PubMed

    Komers, Radko; Plotkin, Horacio

    2016-05-15

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

  10. Classical Renin-Angiotensin System in Kidney Physiology

    PubMed Central

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

    2014-01-01

    The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardio-vascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the “classical” renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the “classical” renin-angiotensin system, with an emphasis on new developments and modern concepts. PMID:24944035

  11. The intracrine renin-angiotensin system.

    PubMed

    Kumar, Rajesh; Thomas, Candice M; Yong, Qian Chen; Chen, Wen; Baker, Kenneth M

    2012-09-01

    The RAS (renin-angiotensin system) is one of the earliest and most extensively studied hormonal systems. The RAS is an atypical hormonal system in several ways. The major bioactive peptide of the system, AngII (angiotensin II), is neither synthesized in nor targets one specific organ. New research has identified additional peptides with important physiological and pathological roles. More peptides also mean newer enzymatic cascades that generate these peptides and more receptors that mediate their function. In addition, completely different roles of components that constitute the RAS have been uncovered, such as that for prorenin via the prorenin receptor. Complexity of the RAS is enhanced further by the presence of sub-systems in tissues, which act in an autocrine/paracrine manner independent of the endocrine system. The RAS seems relevant at the cellular level, wherein individual cells have a complete system, termed the intracellular RAS. Thus, from cells to tissues to the entire organism, the RAS exhibits continuity while maintaining independent control at different levels. The intracellular RAS is a relatively new concept for the RAS. The present review provides a synopsis of the literature on this system in different tissues.

  12. The frail renin-angiotensin system.

    PubMed

    Abadir, Peter M

    2011-02-01

    Over the last few decades, the understanding of the renin-angiotensin system (RAS) has advanced dramatically. RAS is now thought to play a crucial role in physiologic and pathophysiologic mechanisms in almost every organ system and is a key regulator of hypertension, cardiovascular disease, and renal function. Angiotensin II (Ang II) promotes inflammation and the generation of reactive oxygen species and governs onset and progression of vascular senescence, which are all associated with functional and structural changes, contributing to age-related diseases. Although the vast majority of the actions of Ang II, including vascular senescence, are mediated by the Ang II type 1 receptor (AT1R), the identification, characterization, and cloning of the angiotensin type 2 receptor has focused attention on this receptor and to its antagonistic effect on the detrimental effects of AT1R. This review provides an overview of the changes in RAS with aging and age-disease interactions culminating in the development of frailty. PMID:21093722

  13. Hypertension: renin-angiotensin-aldosterone system alterations.

    PubMed

    Te Riet, Luuk; van Esch, Joep H M; Roks, Anton J M; van den Meiracker, Anton H; Danser, A H Jan

    2015-03-13

    Blockers of the renin-angiotensin-aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension. PMID:25767283

  14. The renin-angiotensin system and its blockers.

    PubMed

    Igić, Rajko; Škrbić, Ranko

    2014-01-01

    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. PMID:25731011

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

    ERIC Educational Resources Information Center

    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)

  16. The renin angiotensin system and the metabolic syndrome

    PubMed Central

    Wang, Chih-Hong; Li, Feng; Takahashi, Nobuyuki

    2010-01-01

    The renin angiotensin system (RAS) is important for fluid and blood pressure regulation. Recent studies suggest that an overactive RAS is involved in the metabolic syndrome. This article discusses recent advances on how genetic alteration of the RAS affects cardiovascular and metabolic phenotypes, with a special emphasis on the potential role of angiotensin-independent effects of renin. PMID:21132096

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

    PubMed

    Yoon, Hye Eun; Choi, Bum Soon

    2014-05-01

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

  18. African Americans, hypertension and the renin angiotensin system

    PubMed Central

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

    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. PMID:25276290

  19. The Renin Angiotensin System and the Metabolic Syndrome

    PubMed Central

    de Kloet, Annette D.; Krause, Eric G.; Woods, Stephen C.

    2010-01-01

    The renin angiotensin system (RAS; most well-known for its critical roles in the regulation of cardiovascular function and hydromineral balance) has regained the spotlight for its potential roles in various aspects of the metabolic syndrome. It may serve as a causal link among obesity and several co-morbidities. Drugs that reduce the synthesis or action of angiotensin-II (A-II; the primary effector peptide of the RAS) have been used to treat hypertension for decades and, more recently, clinical trials have determined the utility of these pharmacological agents to prevent insulin resistance. Moreover, there is evidence that the RAS contributes to body weight regulation by acting in various tissues. This review summarizes what is known of the actions of the RAS in the brain and throughout the body to influence various metabolic disorders. Special emphasis is given to the role of the RAS in body weight regulation. PMID:20381510

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

    PubMed

    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.

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

    NASA Technical Reports Server (NTRS)

    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.

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

    DOE PAGES

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

    2006-01-01

    Background . The adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. Methods and results . A panel of mouse models including mice lacking angiotensinogen, Agt ( Agt -KO), mice expressing Agt solely in adipose tissue (aP2- Agt/Agt -KO), and mice overexpressing Agt in adipose tissue (aP2- Agt ) was studied. Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin, and resistin were significantly decreased in Agt -KO mice, while plasma adiponectin levels were increased. aP2- Agt mice exhibited increased adipositymore » 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.« less

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

    PubMed

    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

  4. The Renin Angiotensin Aldosterone System and Insulin Resistance in Humans

    PubMed Central

    Underwood, Patricia C

    2012-01-01

    Alterations in the renin angiotensin aldosterone system (RAAS) contribute to the underlying pathophysiology of insulin resistance in humans; however, individual differences in the treatment response of insulin resistance to RAAS blockade persist. Thus, understanding inter-individual differences in the relationship between the RAAS and insulin resistance may provide insights into improved personalized treatments and improved outcomes. The effects of the systemic RAAS on blood pressure regulation and glucose metabolism have been studied extensively; however, recent discoveries on the influence of local tissue RAAS in the skeletal muscle, heart, vasculature, adipocytes, and pancreas have led to an improved understanding of how activated tissue RAAS influences the development of insulin resistance and diabetes in humans. Angiotensin II (ANGII) is the predominant RAAS component contributing to insulin resistance; however, other players such as aldosterone, renin, and ACE2 are also involved. This review examines the role of local ANGII activity on insulin resistance development in skeletal muscle, adipocytes, and pancreas, followed by a discussion of the other RAAS components implicated in insulin resistance, including ACE2, Ang1-7, renin, and aldosterone. PMID:23242734

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

    PubMed Central

    Shi, Yongyan; Liu, Tianjing; He, Lei; Dougherty, Urszula; Chen, Li; Adhikari, Sarbani; Alpert, Lindsay; Zhou, Guolin; Liu, Weicheng; Wang, Jiaolong; Deb, Dilip K.; Hart, John; Liu, Shu Q.; Kwon, John; Pekow, Joel; Rubin, David T.; Zhao, Qun; Bissonnette, Marc; Li, Yan Chun

    2016-01-01

    The renin-angiotensin system (RAS) plays pathogenic roles in renal and cardiovascular disorders, but whether it is involved in colitis is unclear. Here we show that RenTgMK mice that overexpress active renin from the liver developed more severe colitis than wild-type controls. More than 50% RenTgMK mice died whereas all wild-type mice recovered. RenTgMK mice exhibited more robust mucosal TH17 and TH1/TH17 responses and more profound colonic epithelial cell apoptosis compared to wild-type controls. Treatment with aliskiren (a renin inhibitor), but not hydralazine (a smooth muscle relaxant), ameliorated colitis in RenTgMK mice, although both drugs normalized blood pressure. Chronic infusion of angiotensin II into wild-type mice mimicked the severe colitic phenotype of RenTgMK mice, and treatment with losartan [an angiotensin type 1 receptor blocker (ARB)] ameliorated colitis in wild-type mice, confirming a colitogenic role for the endogenous RAS. In human biopsies, pro-inflammatory cytokines were suppressed in patients with inflammatory bowel disease who were on ARB therapy compared to patients not receiving ARB therapy. These observations demonstrate that activation of the RAS promotes colitis in a blood pressure independent manner. Angiotensin II appears to drive colonic mucosal inflammation by promoting intestinal epithelial cell apoptosis and mucosal TH17 responses in colitis development. PMID:27271344

  6. Renin-angiotensin system in the kidney: What is new?

    PubMed Central

    Ferrão, Fernanda M; Lara, Lucienne S; Lowe, Jennifer

    2014-01-01

    The renin-angiotensin system (RAS) has been known for more than a century as a cascade that regulates body fluid balance and blood pressure. Angiotensin II(Ang II) has many functions in different tissues; however it is on the kidney that this peptide exerts its main functions. New enzymes, alternative routes for Ang IIformation or even active Ang II-derived peptides have now been described acting on Ang II AT1 or AT2 receptors, or in receptors which have recently been cloned, such as Mas and AT4. Another interesting observation was that old members of the RAS, such as angiotensin converting enzyme (ACE), renin and prorenin, well known by its enzymatic activity, can also activate intracellular signaling pathways, acting as an outside-in signal transduction molecule or on the renin/(Pro)renin receptor. Moreover, the endocrine RAS, now is also known to have paracrine, autocrine and intracrine action on different tissues, expressing necessary components for local Ang II formation. This in situ formation, especially in the kidney, increases Ang II levels to regulate blood pressure and renal functions. These discoveries, such as the ACE2/Ang-(1-7)/Mas axis and its antangonistic effect rather than classical deleterious Ang II effects, improves the development of new drugs for treating hypertension and cardiovascular diseases. PMID:25332897

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

    PubMed Central

    Pereira, Regina Maria; dos Santos, Robson Augusto Souza; da Costa Dias, Filipi Leles; Teixeira, Mauro Martins; Silva, Ana Cristina Simões e

    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. PMID:19496186

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

    SciTech Connect

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

    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.

  9. 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.

    PubMed

    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.

  10. Brain renin-angiotensin system and dopaminergic cell vulnerability

    PubMed Central

    Labandeira-García, Jose L.; Garrido-Gil, Pablo; Rodriguez-Pallares, Jannette; Valenzuela, Rita; Borrajo, Ana; Rodríguez-Perez, Ana I.

    2014-01-01

    Although the renin-angiotensin system (RAS) was classically considered as a circulating system that regulates blood pressure, many tissues are now known to have a local RAS. Angiotensin, via type 1 receptors, is a major activator of the NADPH-oxidase complex, which mediates several key events in oxidative stress (OS) and inflammatory processes involved in the pathogenesis of major aging-related diseases. Several studies have demonstrated the presence of RAS components in the basal ganglia, and particularly in the nigrostriatal system. In the nigrostriatal system, RAS hyperactivation, via NADPH-oxidase complex activation, exacerbates OS and the microglial inflammatory response and contributes to progression of dopaminergic degeneration, which is inhibited by angiotensin receptor blockers and angiotensin converting enzyme (ACE) inhibitors. Several factors may induce an increase in RAS activity in the dopaminergic system. A decrease in dopaminergic activity induces compensatory upregulation of local RAS function in both dopaminergic neurons and glia. In addition to its role as an essential neurotransmitter, dopamine may also modulate microglial inflammatory responses and neuronal OS via RAS. Important counterregulatory interactions between angiotensin and dopamine have also been observed in several peripheral tissues. Neurotoxins and proinflammatory factors may also act on astrocytes to induce an increase in RAS activity, either independently of or before the loss of dopamine. Consistent with a major role of RAS in dopaminergic vulnerability, increased RAS activity has been observed in the nigra of animal models of aging, menopause and chronic cerebral hypoperfusion, which also showed higher dopaminergic vulnerability. Manipulation of the brain RAS may constitute an effective neuroprotective strategy against dopaminergic vulnerability and progression of Parkinson’s disease. PMID:25071471

  11. Role of the Collecting Duct Renin Angiotensin System in Regulation of Blood Pressure and Renal Function.

    PubMed

    Ramkumar, Nirupama; Kohan, Donald E

    2016-04-01

    Recent evidence suggests that the renal tubular renin angiotensin system regulates urinary Na(+) and water excretion and blood pressure. Three key components of the tubular renin angiotensin system, namely renin, prorenin receptor, and angiotensin-II type 1 receptor, are localized to the collecting duct. This system may modulate collecting duct Na(+) and water reabsorption via angiotensin-II-dependent and angiotensin-II-independent pathways. Further, the system may be of greatest relevance in hypertensive states and particularly those characterized by high circulating angiotensin-II. In this review, we summarize the current knowledge on the synthesis, regulation, and function of collecting duct-derived renin angiotensin system components and examine recent developments with regard to regulation of blood pressure and renal fluid and Na(+) excretion.

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

    PubMed

    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.

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

    PubMed

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

    2015-08-26

    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 ApoE-deficient atherosclerotic mice.

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

    PubMed Central

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

    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 ApoE-deficient atherosclerotic mice. PMID:26322175

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

    PubMed

    Sheppard, Richard J; Schiffrin, Ernesto L

    2013-04-01

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

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

    PubMed Central

    Takeda, Satoru; Koya, Daisuke; Kanasaki, Keizo

    2015-01-01

    Preeclampsia is a hypertensive disorder that occurs during pregnancy. It has an unknown etiology and affects approximately 5–8% of pregnancies worldwide. The pathophysiology of preeclampsia is not yet known, and preeclampsia has been called “a disease of theories.” The central symptom of preeclampsia is hypertension. However, the etiology of the hypertension is unknown. In this review, we analyze the molecular mechanisms of preeclampsia with a particular focus on the pathogenesis of the 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. PMID:26000015

  17. The renin-angiotensin systems: evolving pharmacological perspectives for cerebroprotection.

    PubMed

    Magy, Laurent; Vincent, François; Faure, Sebastien; Messerli, Franz H; Wang, Jiguang G; Achard, Jean-Michel; Fournier, Albert

    2005-01-01

    During the last 20 years, the renin-angiotensin system (RAS) has become an increasingly important focus of basic and clinical cardiovascular research. One main conceptual step forward was made with the discovery of a tissue RAS and the understanding of its critical pathophysiological role in atherogenesis and plaque destabilisation. Major effort to find new strategies for blocking the RAS has produced new classes of drugs which were expected to be clinically important in the management of hypertension and heart failure. As landmark clinical studies have demonstrated that inhibition of the RAS significantly reduces morbidity and mortality from coronary heart disease, myocardial infarction and heart failure, the concept has rapidly emerged that blocking the RAS was the strategy of choice for preventing cardiovascular diseases. More recently, basic research has however continuously extended our understanding of the complexity of the systemic and tissue RASs, that can no longer be viewed as one-way streets in which one single effector, angiotensin II acts solely through its major (AT1) receptor. Meanwhile, clinical trials have challenged the concept that blocking the RAS is the most effective preventive strategy for all patients and all target organs. Consistent with the recent understanding that the RAS encompasses a number of distinct effectors acting through different receptors to promote opposite effects, a growing body of basic and clinical evidence suggests that blunting the RAS is a double-edge sword, with beneficial effects counterbalanced by deleterious ones, resulting in a net effect that critically depends on the experimental conditions, or the clinical characteristics of the study population. Of particular clinical relevance, a number of clinical trials point to the somewhat provocative conclusion that beyond their blood pressure lowering effect antihypertensive drugs that decrease angiotensin II formation are less stroke protective than the ones that

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

    PubMed

    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.

  19. [Changes in the renin-angiotensin-aldosterone system in elderly patients with chronic ischemic heart disease. 4. The renin-angiotensin-aldosterone system in elderly patients with ischemic heart disease and cardiovascular insufficiency].

    PubMed

    Korkusko, O V; Kalinovskaja, E G; Fedirko, M I; Gidzinskaja, I N

    1989-01-01

    The elderly chronic ischemic heart disease (IHK) patients with cardiac failure show a higher activation of the renin-angiotensin-aldosterone system compared to the younger patients. It was noted functional activity of the renin-angiotensin-aldosterone system increases with a progress of the disease (decompensation). Changes occur not only in the basal level of plasma reninactivity and circulating aldosterone concentration, but also the 24 hour rhythm to the side of an increased hormonal level during the evening hours, evidencing thus for disadaption of the renin-angiotensin-aldosterone system and its decreased reliability under conditions of habitual life activity. Administration of the converting enzyme inhibitor, Captopril, has confirmed a pathogenetic role of the renin-angiotensin-aldosterone system in the development of cardiac failure syndrome in the chronic IHK patients as well as verified a new approach in the treatment of this pathology.

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

    PubMed

    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.

  1. Pharmacological perspectives in sarcopenia: a potential role for renin-angiotensin system blockers?

    PubMed Central

    Sartiani, Laura; Spinelli, Valentina; Laurino, Annunziatina; Blescia, Sabrina; Raimondi, Laura; Cerbai, Elisabetta; Mugelli, lessandro

    2015-01-01

    Summary Sarcopenia represents a major health problem highly prevalent in elderly and age-related chronic diseases. Current pharmacological strategies available to prevent and reverse sarcopenia are largely unsatisfactory thus raising the need to identify novel targets for pharmacological intervention and possibly more effective and safe drugs. This review highlights the current knowledge of the potential benefits of renin-angiotensin system blockade in sarcopenia and discuss the main mechanisms underlying the effects. PMID:26604938

  2. Renin-Angiotensin-Aldosterone System Blockade in Diabetic Nephropathy. Present Evidences

    PubMed Central

    Lozano-Maneiro, Luz; Puente-García, Adriana

    2015-01-01

    Diabetic Kidney Disease (DKD) is the leading cause of chronic kidney disease in developed countries and its prevalence has increased dramatically in the past few decades. These patients are at an increased risk for premature death, cardiovascular disease, and other severe illnesses that result in frequent hospitalizations and increased health-care utilization. Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and the development of end-stage renal disease remain major concerns in diabetes. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) results in progressive renal damage. RAAS blockade is the cornerstone of treatment of DKD, with proven efficacy in many arenas. The theoretically-attractive option of combining these medications that target different points in the pathway, potentially offering a more complete RAAS blockade, has also been tested in clinical trials, but long-term outcomes were disappointing. This review examines the “state of play” for RAAS blockade in DKD, dual blockade of various combinations, and a perspective on its benefits and potential risks. PMID:26569322

  3. [Changes in the renin-angiotensin-aldosterone system in elderly patients with chronic ischemic heart disease. 3. The renin-angiotensin-aldosterone system in elderly patients with ischemic heart disease without cardiovascular failure].

    PubMed

    Korkusko, V; Kalinovskaja, E G; Fedirko, M I; Gidzinskaja, I N

    1989-01-01

    As shown by the results of the investigation, there is a moderate rise in renin-angiotensin-aldosterone system activity in the elderly patients suffering from chronic IHK under normal conditions of life: basal level, changes in plasma renin activity and circulating aldosterone concentration during a 24-hour period and in response to the orthostasis. Considerable disturbances of the functional state of the renin-angiotensin-aldosterone system are seen with a physical load of the submaximal intensity. The data obtained indicate pathogenetic significance of the above changes which should be taken into consideration while prescribing therapy of such patients.

  4. The past, present and future of renin-angiotensin aldosterone system inhibition.

    PubMed

    Mentz, Robert J; Bakris, George L; Waeber, Bernard; McMurray, John J V; Gheorghiade, Mihai; Ruilope, Luis M; Maggioni, Aldo P; Swedberg, Karl; Piña, Ileana L; Fiuzat, Mona; O'Connor, Christopher M; Zannad, Faiez; Pitt, Bertram

    2013-09-01

    The renin-angiotensin aldosterone system (RAAS) is central to the pathogenesis of cardiovascular disease. RAAS inhibition can reduce blood pressure, prevent target organ damage in hypertension and diabetes, and improve outcomes in patients with heart failure and/or myocardial infarction. This review presents the history of RAAS inhibition including a summary of key heart failure, myocardial infarction, hypertension and atrial fibrillation trials. Recent developments in RAAS inhibition are discussed including implementation and optimization of current drug therapies. Finally, ongoing clinical trials, opportunities for future trials and issues related to the barriers and approvability of novel RAAS inhibitors are highlighted.

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

    PubMed

    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

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

    PubMed

    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

  7. Do genetic variants of the Renin-Angiotensin system predict blood pressure response to Renin-Angiotensin system-blocking drugs?: a systematic review of pharmacogenomics in the Renin-Angiotensin system.

    PubMed

    Konoshita, Tadashi

    2011-10-01

    The concept of "pharmacogenomics" or "pharmacogenetics" promises to offer the ultimate in personalized medicine, and the renin-angiotensin system (RAS) is one of the most plausible candidates for the application of this approach in the area of hypertension. For the past two decades, genetic variants of the RAS have been tested for association with blood pressure response, but the results have been inconsistent. The problems have been attributed to many issues, but the most fundamental concern is thought to be the statistical power of the studies. Therefore, we have tried to put together a new systematic review using a database search including only recent reports with adequate numbers of subjects, and 11 reports were identified. From the results, we were able to draw conclusions with nearly consistent findings that the conventional genetic variants of the system (i.e., the ACE I/D, AGT M235T, AT1 A1166C, and AT2 variant) are not associated with antihypertensive effects by RAS blockade, at least by one individual SNP. By contrast, significant associations have been reported (by one report each) for AGT rs7079, AT1 haplotype, REN, and ACE2. For these variants, further evaluations and confirmation are anticipated. PMID:21562941

  8. Role of renin-angiotensin system in hypotension-evoked thirst: studies with hydralazine.

    PubMed

    Stocker, S D; Sved, A F; Stricker, E M

    2000-08-01

    Injection of rats either with diazoxide (25 mg/kg iv), isoproterenol (0.33 mg/kg sc), or hydralazine (HDZ) (10 mg/kg ip) decreased arterial blood pressure from approximately 120 to 70-80 mmHg and stimulated renin secretion. However, diazoxide and isoproterenol treatments each stimulated water ingestion, whereas HDZ treatment did not. HDZ treatment did not reduce water intake evoked by systemic injection of hypertonic saline or 20% polyethylene glycol solution or by 24-h water deprivation, suggesting that HDZ treatment did not interfere with drinking behavior. In contrast, HDZ treatment markedly reduced water intake evoked by injection of diazoxide or isoproterenol or by intravenous infusion of renin. Furthermore, a highly significant correlation was observed when plasma ANG II levels were plotted as a function of plasma renin activity after intravenous infusion of renin and after diazoxide and isoproterenol treatments. However, values obtained after HDZ treatment alone or in combination with intravenous infusion of renin did not fall near the 99% confidence interval of the regression line, suggesting that HDZ treatment blocks ANG II production and/or promotes its clearance. Thus rats apparently do not increase water intake after HDZ treatment, because this drug interferes with the renin-angiotensin system. These results provide further evidence that arterial hypotension evokes thirst in rats predominantly by activation of the renin-angiotensin system.

  9. The renin-angiotensin system: a possible contributor to migraine pathogenesis and prophylaxis.

    PubMed

    Ripa, Patrizia; Ornello, Raffaele; Pistoia, Francesca; Carolei, Antonio; Sacco, Simona

    2014-09-01

    The presence of a tissue-based renin-angiotensin system, independent of the systemic one, has been identified in several organs including the brain. Experimental models have suggested the involvement of the renin-angiotensin system in neurogenic inflammation, susceptibility to oxidative stress, endothelial dysfunction, and neuromodulation of nociceptive transmission, thus potentially contributing to the pathogenesis of migraine. Genetic factors that increase susceptibility to migraine may include angiotensin-converting enzyme polymorphism, although available data are controversial. Clinical studies have suggested that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be effective in migraine prophylaxis. However, further research should clarify whether the postulated preventive effect is attributable to a pharmacological action over and above the antihypertensive effect and should test their tolerability in subjects with normal blood pressure values. In patients with contraindications or not responding to conventional prophylactic drugs and in patients with comorbid arterial hypertension, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be used for migraine prophylaxis.

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

    PubMed

    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.

  11. Renal implications of the renin-angiotensin-aldosterone system blockade in heart failure.

    PubMed

    Ruilope, L M; Barrios, V; Volpe, M

    2000-11-01

    The renin-angiotensin-aldosterone system actively participates in the derangement of renal function since the early stages of heart failure (HF). A diminished capacity to excrete sodium secondary to increased proximal tubular re-absorption and loss of the renal functional reserve are the two most relevant initial alterations of renal function in which angiotensin II has been proven to act directly. Meanwhile, the octapeptide contributes to maintain glomerular filtration rate (GFR) within normal limits through efferent arteriole vasoconstriction. Administration of angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor antagonists (ARA) may thus be accompanied by a functional fall in that parameter. Advanced age, higher initial serum creatinine, history of hypertension, diabetes and atrial fibrillation predict the onset of GFR impairment associated with blockade of the renin-angiotensin system. Concomitant administration of betablockers may help to protect renal function, and preliminary data indicate that the combination of ACEi and ARA is not accompanied by a higher renal risk. The good prognostic effects of aldosterone antagonists in HF does not seem to be related to intrarenal effects of these compounds with the exception of preventing potassium loss and hypokalemia. The systematic therapeutic use of drug(s) provided with beneficial renal effects, to treat arterial hypertension or myocardial ischemia, may contribute to delay of, or prevent the development of HF.

  12. The Uterine Placental Bed Renin-Angiotensin System in Normal and Preeclamptic Pregnancy

    PubMed Central

    Anton, Lauren; Merrill, David C.; Neves, Liomar A. A.; Diz, Debra I.; Corthorn, Jenny; Valdes, Gloria; Stovall, Kathryn; Gallagher, Patricia E.; Moorefield, Cheryl; Gruver, Courtney; Brosnihan, K. Bridget

    2009-01-01

    Previously, we demonstrated activation of the renin-angiotensin system in the fetal placental chorionic villi, but it is unknown whether the immediately adjacent area of the maternal uterine placental bed is regulated similarly. This study measured angiotensin peptides, renin-angiotensin system component mRNAs, and receptor binding in the fundus from nonpregnant subjects (n = 19) and in the uterine placental bed from normal (n = 20) and preeclamptic (n = 14) subjects. In the uterine placental bed from normal pregnant women, angiotensin II peptide levels and angiotensinogen, angiotensin-converting enzyme, angiotensin receptor type 1 (AT1), AT2, and Mas mRNA expression were lower as compared with the nonpregnant subjects. In preeclamptic uterine placental bed, angiotensin II peptide levels and renin and angiotensin-converting enzyme mRNA expression were significantly higher than normal pregnant subjects. The AT2 receptor was the predominant receptor subtype in the nonpregnant fundus, whereas all angiotensin receptor binding was undetectable in normal and preeclamptic pregnant uterine placental bed compared with nonpregnant fundus. These findings suggest that the maternal uterine placental bed may play an endocrine role by producing angiotensin II, which acts in the adjacent placenta to vasoconstrict fetal chorionic villi vessels where we have shown previously that AT1 receptors predominate. This would lead to decreased maternal-fetal oxygen exchange and fetal nutrition, a known characteristic of preeclampsia. PMID:19520788

  13. Pleiotrophin is an important regulator of the renin-angiotensin system in mouse aorta.

    PubMed

    Herradon, Gonzalo; Ezquerra, Laura; Nguyen, Trang; Vogt, Thomas F; Bronson, Roderick; Silos-Santiago, Inmaculada; Deuel, Thomas F

    2004-11-19

    To better understand the phenotype of pleiotrophin (PTN the protein, Ptn the gene) genetically deficient mice (Ptn -/-), we compared the transcriptional profiles of aortae obtained from Ptn -/- and wild type (WT, Ptn +/+) mice using a 14,400 gene microarray chip (Affymetrix) and confirmed the analysis of relevant genes by real time RT-PCR. We found striking alterations in expression levels of different genes of the renin-angiotensin system of Ptn -/- mice relative to WT (Ptn +/+) mice. The mRNA levels of the angiotensin converting enzyme (ACE) were significantly decreased in Ptn -/- mice whereas the mRNA levels of the angiotensin II type 1 (AT1) and angiotensin II type 2 (AT2) receptors were significantly increased in Ptn -/- mice when they were compared with mRNA levels in WT (Ptn +/+) mice aortae. These data demonstrate for the first time that the levels of expression of the Ptn gene markedly influence expression levels of the genes encoding the key proteins of the renin-angiotensin system in mouse aorta and suggest the tentative conclusion that levels of Ptn gene expression have the potential to critically regulate the downstream activities of angiotensin II, through the regulation of its synthesis by ACE and its receptor mediated functions through regulation of both the AT1 and AT2 receptors.

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

    PubMed

    Malik, Umar; Raizada, Veena

    2015-01-01

    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.

  15. Off the beaten renin-angiotensin-aldosterone system pathway: new perspectives on antiproteinuric therapy.

    PubMed

    Gordon, Judit; Kopp, Jeffrey B

    2011-07-01

    CKD is a major public health problem in the developed and the developing world. The degree of proteinuria associated with renal failure is a generally well accepted marker of disease severity. Agents with direct antiproteinuric effects are highly desirable therapeutic strategies for slowing, or even halting, progressive loss of kidney function. We review progress on therapies acting further downstream of the renin-angiotensin-aldosterone system pathway (e.g., transforming growth factor-beta antagonism, endothelin antagonism) and on those acting independent of the renin-angiotensin-aldosterone system pathway. In all, we discuss 26 therapeutic targets or compounds and 2 lifestyle changes (dietary modification and weight loss) that have been used clinically for diabetic or nondiabetic kidney disease. These therapies include endogenous molecules (estrogens, isotretinoin), biologic antagonists (monoclonal antibodies, soluble receptors), and small molecules. Where mechanistic data are available, these therapies have been shown to exert favorable effects on glomerular cell phenotype. In some cases, recent work has indicated surprising new molecular pathways for some therapies, such as direct effects on the podocyte by glucocorticoids, rituximab, and erythropoietin. It is hoped that recent advances in the basic science of kidney injury will prompt development of more effective pharmaceutical and biologic therapies for proteinuria.

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

    PubMed

    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

  17. Local renin-angiotensin system mediates endothelial dilator dysfunction in aging arteries.

    PubMed

    Flavahan, Sheila; Chang, Fumin; Flavahan, Nicholas A

    2016-09-01

    Aging impairs endothelium-dependent NO-mediated dilatation, which results from increased production of reactive oxygen species (ROS). The local generation of angiotensin II (ANG II) is increased in aging arteries and contributes to inflammatory and fibrotic activity of smooth muscle cells and arterial wall remodeling. Although prolonged in vivo ANG II inhibition improves the impaired endothelial dilatation of aging arteries, it is unclear whether this reflects inhibition of intravascular or systemic ANG II systems. Experiments were therefore performed on isolated tail arteries from young (3-4 mo) and old (22-24 mo) F344 rats to determine if a local renin-angiotensin system contributes to the endothelial dilator dysfunction of aging. Aging impaired dilatation to the endothelial agonist acetylcholine but did not influence responses to a nitric oxide (NO) donor (DEA NONOate). Dilatation to acetylcholine was greatly reduced by NO synthase inhibition [nitro-l-arginine methyl ester (l-NAME)] in young and old arteries. In isolated arteries, acute inhibition of angiotensin-converting enzyme (ACE) (perindoprilat), renin (aliskiren), or AT1 receptors (valsartan, losartan) did not influence dilatation to acetylcholine in young arteries but increased responses in old arteries. After ANG II inhibition, the dilator response to acetylcholine was similar in young and old arteries. ROS activity, which was increased in endothelium of aging arteries, was also reduced by inhibiting ANG II (perindoprilat, losartan). Renin expression was increased by 5.6 fold and immunofluorescent levels of ANG II were confirmed to be increased in aging compared with young arteries. Exogenous ANG II inhibited acetylcholine-induced dilatation. Therefore, aging-induced impairment of endothelium-dependent dilatation in aging is caused by a local intravascular renin-angiotensin system.

  18. The Brain Renin-Angiotensin System Controls Divergent Efferent Mechanisms to Regulate Fluid and Energy Balance

    PubMed Central

    Grobe, Justin L.; Grobe, Connie L.; Beltz, Terry G.; Westphal, Scott G.; Morgan, Donald A.; Xu, Di; de Lange, Willem J.; Li, Huiping; Sakai, Koji; Thedens, Daniel R.; Cassis, Lisa A.; Rahmouni, Kamal; Mark, Allyn L.; Johnson, Alan Kim; Sigmund, Curt D.

    2010-01-01

    Summary The renin-angiotensin system (RAS), in addition to its endocrine functions, plays a role within individual tissues such as the brain. The brain RAS is thought to control blood pressure through effects on fluid intake, vasopressin release and sympathetic nerve activity (SNA), and may regulate metabolism through mechanisms which remain undefined. We used a double-transgenic mouse model that exhibits brain-specific RAS activity to examine mechanisms contributing to fluid and energy homeostasis. The mice exhibit high fluid turnover through increased adrenal steroids, which is corrected by adrenalectomy and attenuated by mineralocorticoid receptor blockade. They are also hyperphagic but lean because of a marked increase in body temperature and metabolic rate, mediated by increased SNA and suppression of the circulating RAS. β-adrenergic blockade or restoration of circulating angiotensin-II, but not adrenalectomy, normalized metabolic rate. Our data point to contrasting mechanisms by which the brain RAS regulates fluid intake and energy expenditure. PMID:21035755

  19. Role of the Renin-Angiotensin System and Aldosterone on Cardiometabolic Syndrome

    PubMed Central

    Stiefel, P.; Vallejo-Vaz, A. J.; García Morillo, S.; Villar, J.

    2011-01-01

    Aldosterone facilitates cardiovascular damage by increasing blood pressure and through different mechanisms that are independent of its effects on blood pressure. In this respect, recent evidence involves aldosterone in the pathogenesis of metabolic syndrome. Although this relationship is complex, there is some evidence suggesting that different factors may play an important role, such as insulin resistance, renin-angiotensin-aldosterone system, oxidative stress, sodium retention, increased sympathetic activity, levels of free fatty acids, or inflammatory cytokines and adipokines. In addition to the classical pathway by which aldosterone acts through the mineralocorticoid receptors leading to sodium retention, aldosterone also has other mechanisms that influence cardiovascular tissue remodelling. Finally, overweight and obesity promote the adrenal secretion of aldosterone, increasing the predisposition to type 2 diabetes mellitus. Further studies are needed to better establish therapeutic strategies that act on the blockade of mineralocorticoid receptor in the treatment and prevention of cardiovascular diseases related to the excess of aldosterone and the metabolic syndrome. PMID:21785705

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

    PubMed

    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.

  1. Effects of Renin-Angiotensin-Aldosterone System Blockade in Patients with End-Stage Renal Disease.

    PubMed

    Slomka, Teresa; Lennon, Emily S; Akbar, Hina; Gosmanova, Elvira O; Bhattacharya, Syamal K; Oliphant, Carrie S; Khouzam, Rami N

    2016-03-01

    Blockers of the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are routinely used in patients with chronic kidney disease because of their cardiovascular (CV) and renoprotective effects. However, there are no uniform recommendations about RAAS blockers for CV protection in the end-stage renal disease (ESRD) population other than the preferred drug class for blood pressure control. This uncertainty stems from the fact that patients with ESRD were generally excluded from randomized controlled trials evaluating the cardioprotective benefits of RAAS blockers. It is important to weigh the potential harms associated with the use of RAAS blockers, such as electrolyte disturbances and worsening anemia, with their role in protection of residual kidney function, alleviation of thirst and potential CV benefits. The objective of this review is to summarize the current knowledge about the use of RAAS blockers in patients with ESRD. PMID:26992264

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

    PubMed

    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.

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

    PubMed Central

    Gismondi, Ronaldo Altenburg; Bedirian, Ricardo; Pozzobon, Cesar Romaro; Ladeira, Márcia Cristina; Oigman, Wille; Neves, Mário Fritsch

    2015-01-01

    Background 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. PMID:26465872

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

    PubMed

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

    2013-01-01

    The current epidemic of obesity and type 2 diabetes is attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. More than two thirds of diabetic patients have hypertension. Methylglyoxal is a highly reactive dicarbonyl generated during glucose and fructose metabolism, and a major precursor of advanced glycation end products (AGEs). Plasma methylglyoxal levels are increased in hypertensive rats and diabetic patients. Our aim was to examine the levels of methylglyoxal, mediators of the renin angiotensin system and blood pressure in male Sprague-Dawley rats treated with a high fructose diet (60% of total calories) for 4 months. The thoracic aorta and kidney were used for molecular studies, along with cultured vascular smooth muscle cells (VSMCs). HPLC, Western blotting and Q-PCR were used to measure methylglyoxal and reduced glutathione (GSH), proteins and mRNA, respectively. Fructose treated rats developed a significant increase in blood pressure. Methylglyoxal level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE) and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of methylglyoxal were attenuated by metformin, a methylglyoxal scavenger and AGEs inhibitor. In conclusion, we report a strong association between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats. PMID:24040205

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

    NASA Technical Reports Server (NTRS)

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

    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 renin-angiotensin system is related to LBNP tolerance. Healthy men (2,822 cal/day(exp -1), 2 mmol*kg(exp -1)*day(exp -1)) Na(+)) were exposed to 30 minutes of progressive LBNP to -50 mmHg. LBNP was uneventful for seven men (25 +/- 2 years, HiTol group), but eight men (26 +/- 3 years) reached pre-syncope after 11 +/- 1 minutes (P < 0.001, LoTol group). Mean arterial pressure was unchanged. Central venous pressure and left atrial diameter decreased in both groups (5-6 mmHg by approx. 30%, P < 0.05). Control [hormone] were similar but, pRA differed between groups (LoTol 0.6 +/- 0.1, HiTol 1.2 +/- 0.1 ng Ang1/(ml(exp -1)*h(exp -1)), P < 0.05). LBNP increased (P < 0.05) pRA and pATII more in HiTol (9.9 +/- 2.2 ng Ang1/(ml(exp -1)*h(exp -1)) and 58 +/- 12 pg/ml(exp -1)) than LoTol (4.3 +/- 0.9 ng Ang1/(ml*h) and 28 +/- 6 pg/ml(exp -1)). In contrast, pVP was higher (P < 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.

  6. Activation of the intrarenal renin-angiotensin-system in murine polycystic kidney disease

    PubMed Central

    Saigusa, Takamitsu; Dang, Yujing; Bunni, Marlene A; Amria, May Y; Steele, Stacy L; Fitzgibbon, Wayne R; Bell, P Darwin

    2015-01-01

    The mechanism for early hypertension in polycystic kidney disease (PKD) has not been elucidated. One potential pathway that may contribute to the elevation in blood pressure in PKD is the activation of the intrarenal renin-angiotensin-system (RAS). For example, it has been shown that kidney cyst and cystic fluid contains renin, angiotensin II (AngII), and angiotensinogen (Agt). Numerous studies suggest that ciliary dysfunction plays an important role in PKD pathogenesis. However, it is unknown whether the primary cilium affects the intrarenal RAS in PKD. The purpose of this study was to determine whether loss of cilia or polycystin 1 (PC1) increases intrarenal RAS in mouse model of PKD. Adult Ift88 and Pkd1 conditional floxed allele mice with or without cre were administered tamoxifen to induce global knockout of the gene. Three months after tamoxifen injection, kidney tissues were examined by histology, immunofluorescence, western blot, and mRNA to assess intrarenal RAS components. SV40 immortalized collecting duct cell lines from hypomorphic Ift88 mouse were used to assess intrarenal RAS components in collecting duct cells. Mice without cilia and PC1 demonstrated increased kidney cyst formation, systolic blood pressure, prorenin, and kidney and urinary angiotensinogen levels. Interestingly immunofluorescence study of the kidney revealed that the prorenin receptor was localized to the basolateral membrane of principal cells in cilia (−) but not in cilia (+) kidneys. Collecting duct cAMP responses to AngII administration was greater in cilia (−) vs. cilia (+) cells indicating enhanced intrarenal RAS activity in the absence of cilia. These data suggest that in the absence of cilia or PC1, there is an upregulation of intrarenal RAS components and activity, which may contribute to elevated blood pressure in PKD. PMID:25999403

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

    PubMed

    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

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

    PubMed

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

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

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

    PubMed

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

    Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events. PMID:25439533

  10. Potential role of renin-angiotensin system blockade for preventing myocardial ischemia/reperfusion injury and remodeling after myocardial infarction.

    PubMed

    Dai, Wangde; Kloner, Robert A

    2011-03-01

    Experimental and clinical studies have demonstrated that myocardial ischemia induces activation of various components of the renin-angiotensin system (RAS), including angiotensinogen, renin, angiotensin-converting enzyme (ACE), angiotensins, and angiotensin receptors, in the acute phase of myocardial infarction and the postinfarction remodeling process. Pharmacological inhibition of the RAS by administration of renin inhibitors, ACE inhibitors, and angiotensin receptor blockers has shown beneficial effects on the pathological processes of myocardial infarction in both experimental animal studies and clinical trials. However, the potential mechanisms responsible for the cardioprotection of RAS inhibition remain unclear. In this review, we discuss roles of RAS blocking in the prevention of myocardial ischemia/reperfusion injury and postinfarction remodeling.

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

    PubMed

    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.

  12. Renin-Angiotensin System Inhibition in Conscious Dogs during Acute Hypoxemia

    PubMed Central

    Liang, Chang-Seng; Gavras, Haralambos

    1978-01-01

    The role of the renin-angiotensin system in mediating the circulatory and metabolic responses to hypoxia was studied in three groups of conscious dogs that were infused continuously with normal saline, teprotide (10 μg/kg per min), and saralasin (1 μg/kg per min), respectively. Hypoxia was produced by switching from breathing room air to 5 or 8% oxygen-nitrogen mixture. Plasma renin activity increased from 2.3±0.4 to 4.9±0.8 ng/ml per h during 8% oxygen breathing, and from 2.8±0.4 to 8.4±1.8 ng/ml per h during 5% oxygen breathing. As expected, cardiac output, heart rate, mean aortic blood pressure, and left ventricular dP/dt and dP/dt/P increased during both 5 and 8% oxygen breathing in the saline-treated dogs; greater increases occurred during the more severe hypoxia. Teprotide and saralasin infusion diminished the hemodynamic responses to 5% oxygen breathing, but did not affect the responses to 8% oxygen breathing significantly. In addition, the increased blood flows to the myocardium, kidneys, adrenals, brain, intercostal muscle, and diaphragm that usually occur during 5% oxygen breathing were reduced by both agents. These agents also reduced the increases in plasma norepinephrine concentration during 5% oxygen breathing, but had no effects on tissue aerobic or anaerobic metabolism. In dogs pretreated with propranolol and phentolamine, administration of teprotide (0.5 mg/kg) during 5% oxygen breathing reduced mean aortic blood pressure and total peripheral vascular resistance, and increased cardiac output and heart rate, but did not affect left ventricular dP/dt, dP/dt/P, and end-diastolic pressure. Simultaneously, renal and myocardial blood flows increased and myocardial oxygen extraction decreased, while myocardial oxygen consumption did not change significantly. These results suggest that the renin-angiotensin system plays an important role in the hemodynamic responses to severe hypoxia. It appears that angiotensin not only exerts a direct

  13. Different cross-talk sites between the renin-angiotensin and the kallikrein-kinin systems.

    PubMed

    Su, Jin Bo

    2014-12-01

    Targeting the renin-angiotensin system (RAS) constitutes a major advance in the treatment of cardiovascular diseases. Evidence indicates that angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers act on both the RAS and the kallikrein-kinin system (KKS). In addition to the interaction between the RAS and KKS at the level of angiotensin-converting enzyme catalyzing both angiotensin II generation and bradykinin degradation, the RAS and KKS also interact at other levels: 1) prolylcarboxypeptidase, an angiotensin II inactivating enzyme and a prekallikrein activator; 2) kallikrein, a kinin-generating and prorenin-activating enzyme; 3) angiotensin-(1-7) exerts kininlike effects and potentiates the effects of bradykinin; and 4) the angiotensin AT1 receptor forms heterodimers with the bradykinin B2 receptor. Moreover, angiotensin II enhances B1 and B2 receptor expression via transcriptional mechanisms. These cross-talks explain why both the RAS and KKS are up-regulated in some circumstances, whereas in other circumstances both systems change in the opposite manner, expressed as an activated RAS and a depressed KKS. As the cross-talks between the RAS and the KKS play an important role in response to different stimuli, taking these cross-talks between the two systems into account may help in the development of drugs targeting the two systems. PMID:23386283

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    Sabharwal, Rasna; Chapleau, Mark W

    2014-04-01

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

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

    PubMed

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

    2015-07-01

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

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

    PubMed

    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.

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

    PubMed

    Williams, Bryan

    2016-06-01

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

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

    PubMed

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

    2015-09-01

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

  1. Obesity and cardiovascular disease: role of adipose tissue, inflammation, and the renin-angiotensin-aldosterone system.

    PubMed

    Lastra, Guido; Sowers, James R

    2013-09-01

    Obesity is a leading contributor to morbidity and mortality worldwide. Chronic overnutrition and lack of physical activity result in excess deposition of adipose tissue and insulin resistance, which plays a key role in the pathophysiology of type 2 diabetes mellitus (DM2) and associated cardiovascular disease (CVD). Dysfunctional adipose tissue in obese individuals is characterized by chronic low-grade inflammation that spreads to several tissues as well as systemically and is able to impact the cardiovascular system, resulting in both functional and anatomical abnormalities. Inflammation is characterized by abnormalities in both innate and adaptive immunity including adipose tissue infiltration by CD4+ T lymphocytes, pro-inflammatory (M1) macrophages, and increased production of adipokines. The renin-angiotensin-aldosterone system (RAAS) is inappropriately activated in adipose tissue and contributes to originating and perpetuating inflammation and excessive oxidative stress by increasing production of reactive oxygen species (ROS). In turn, ROS and pro-inflammatory adipokines cause resistance to the metabolic actions of insulin in several tissues including cardiovascular and adipose tissue. Insulin resistance in cardiovascular tissues is characterized by impaired vascular reactivity and abnormal cardiac contractility as well as hypertrophy, fibrosis, and remodeling, which ultimately result in CVD. In this context, weight loss through caloric restriction, regular physical activity, and surgery as well as pharmacologic RAAS blockade all play a key role in reducing obesity-related cardiovascular morbidity and mortality.

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

    PubMed Central

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

    2015-01-01

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

  3. The renin-angiotensin-aldosterone system and the eye in diabetes.

    PubMed

    Strain, W David; Chaturvedi, Nish

    2002-12-01

    Diabetic retinopathy is the leading cause of blindness in the under 65s, and with the burden of disease case load expected to exceed 200 million worldwide within 10 years, much effort is being spent on prophylactic interventions. Early work focused on improving glycaemic control; however, with the publication of EURODIAB Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) and United Kingdom Prospective Diabetes Study (UKPDS), the focus has recently moved to control of blood pressure and specifically the renin-angiotensin system (RAS). There is a large body of evidence for a local RAS within the eye that is activated in diabetes. This appears to be directly responsible, as well as indirectly through other mediators, for an increase in concentration of vascular endothelial growth factor (VEGF), a selective angiogenic and vasopermeability factor that is implicated in the pathogenesis of diabetic retinopathy. Inhibition of angiotensin-converting enzyme appears to reduce concentrations of VEGF, with a concurrent anti-proliferative effect independent of systemic VEGF levels or blood pressure. Angiotensin II (Ang II) Type 1 (AT(1)) receptor blockade has been shown to reduce neovascularisation independent of VEGF levels in animal models. This may be due to antagonism of activation of mitogen-activated protein kinase, which is a potent cellular proliferation stimulator, by Ang II, although this needs further evaluation.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

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

    2015-05-01

    Skeletal muscle is a tissue that shows the most plasticity in the body; it can change in response to physiological and pathological stimuli. Among the diseases that affect skeletal muscle are myopathy-associated fibrosis, insulin resistance, and muscle atrophy. A common factor in these pathologies is the participation of the renin-angiotensin system (RAS). This system can be functionally separated into the classical and nonclassical RAS axis. The main components of the classical RAS pathway are angiotensin-converting enzyme (ACE), angiotensin II (Ang-II), and Ang-II receptors (AT receptors), whereas the nonclassical axis is composed of ACE2, angiotensin 1-7 [Ang (1-7)], and the Mas receptor. Hyperactivity of the classical axis in skeletal muscle has been associated with insulin resistance, atrophy, and fibrosis. In contrast, current evidence supports the action of the nonclassical RAS as a counter-regulator axis of the classical RAS pathway in skeletal muscle. In this review, we describe the mechanisms involved in the pathological effects of the classical RAS, advances in the use of pharmacological molecules to inhibit this axis, and the beneficial effects of stimulation of the nonclassical RAS pathway on insulin resistance, atrophy, and fibrosis in skeletal muscle. PMID:25764065

  7. Chronic ethanol intake modifies renin-angiotensin system-regulating aminopeptidase activities in mouse cerebellum.

    PubMed

    Mayas, M D; Ramírez-Expósito, M J; García, M J; Carrera, M P; Cobo, M; Camacho, B; Martínez Martos, J M

    2005-04-01

    In developing cerebellum, where critical periods of vulnerability have been established for several basic substances, it has been extensively studied the wide array of abnormalities induced by exposure to ethanol (EtOH). However, little is known about the effects of EtOH consumption on cerebellar functions in adult individuals. Several studies show participation in cognitive activities to be concentrated in the lateral cerebellum (hemispheres), whereas basic motor functions such as balance and coordination are represented in the medial parts of the cerebellum (vermis and paravermis). In addition to the circulating renin angiotensin system (RAS), a local system has been postulated in brain. The effector peptides of the RAS are formed via the activity of several aminopeptidases (AP). The present work analyses the effect of chronic EtOH intake on the RAS-regulating AP activities in the soluble and membrane-bound fractions of two cerebellar locations: the hemispheres and the vermis. We hypothesize that cerebellar RAS is involved in basic motor functions rather than in cognitive activities.

  8. [INTERACTION OF BETA-BLOCKER PROPRANOLOL WITH RENIN-ANGIOTENSIN SYSTEM INHIBITORS IN RAT KIDNEY].

    PubMed

    Kuzmin, O B; Buchneva, N V; Landar, L N

    2016-01-01

    Propranolol injection (0.5 mg/kg, s.c.) in anesthetized rats increases diuresis 1.60 times (p < 0.05) with simultaneous 1.54- and 1.62-fold increase (p < 0.05) in sodium and potassium excretion, respectively. Preliminary inhibition of renin-angiotensin system (RAS) activity using ACE inhibitor enalapril (1 mg/kg, orally, 7 days) increases the sensitivity of rat kidney to drug, increasing its diuretic effect 2.33 times, natriuresis 2.49 times, and urine potassium excretion 1.80 times (p < 0.05). After the preliminary insertion of AT1 angiotensin receptor antagonist losartan (1 mg/kg, orally, 7 days), propranolol causes 1.8-fold increase in diuresis, 2.48-fold decrease in urine sodium, and 1.71-fold decrease in kaliuresis (p < 0.05). Preliminary administration of direct renin inhibitor aliskiren (4 mg/kg, orally, 7 days) is accompanied by 2.30-fold increase in the diuretic effect of propranolol, 2.56-fold increase in natriuresis, and 2.27-fold increase in urine potassium excretion (p < 0.05). It is concluded that the renal tissue RAS is involved in the mechanism of propranolol action in the kidney, acting as modulator preventing excessive loss of water and electrolytes with urine. PMID:27455575

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

    PubMed Central

    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

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

    PubMed

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

    2012-05-01

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

  11. The plasma renin-angiotensin system in preeclampsia: effects of magnesium sulfate.

    PubMed

    Sipes, S L; Weiner, C P; Gellhaus, T M; Goodspeed, J D

    1989-06-01

    Two groups of women were studied in a prospective longitudinal fashion to determine the effects of a 2.5-hour infusion of magnesium sulfate upon the renin-angiotensin system. Serum magnesium concentration, angiotensin-converting enzyme concentration, and plasma renin activity were measured at uniform intervals in women with either preeclampsia or preterm labor. Plasma renin activity was significantly lower (3.9 +/- 2.2 versus 6.1 +/- 1.8 ng/mL/minute; P = .004) and angiotensin-converting enzyme significantly higher (47.1 +/- 14 versus 34.0 +/- 10 U/mL; P = .008) in women with preeclampsia than in those with preterm labor. Magnesium infusion was associated with a sustained decline in plasma renin activity in preeclamptic women (P = .003). A transient decline in angiotensin-converting enzyme (P = .009) was observed in women with preeclampsia, but not with preterm labor. In contrast to the sustained change in plasma renin activity, angiotensin-converting enzyme concentration returned to baseline activity levels by 2.5 hours. A nonsignificant negative relationship (P = .06) was noted between angiotensin-converting enzyme and gestational age in subjects with preeclampsia. We conclude that a short-term infusion of magnesium sulfate leads to a sustained decline in plasma renin activity in preeclamptic women, but exerts no sustained effect on angiotensin-converting enzyme in women with either preeclampsia or preterm labor.

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

    PubMed

    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.

  13. The retinal renin-angiotensin system: implications for therapy in diabetic retinopathy.

    PubMed

    Sjølie, A K; Chaturvedi, N

    2002-08-01

    Retinopathy is the most common complication of diabetes, and a leading cause of blindness in people of working age. Optimal blood pressure and metabolic control can reduce the risk of diabetic retinopathy, but are difficult to achieve in clinical practice. In the EUCLID Study, the angiotensin converting enzyme (ACE) inhibitor lisinopril reduced the risk of progression of retinopathy by approximately 50%, and also significantly reduced the risk of progression to proliferative retinopathy. These findings are consistent with extensive evidence that the renin-angiotensin system is expressed in the eye, and that adverse effects of angiotensin II on retinal angiogenesis and function can be inhibited by ACE inhibitors or angiotensin II-receptor blockers. However, in the EUCLID Study retinopathy was not a primary end-point and the study was not sufficiently powered for the eye-related outcomes. Hence, the Diabetic Retinopathy Candesartan Trials (DIRECT) programme has been established to determine whether AT(1)-receptor blockade with candesartan can prevent the incidence and progression of diabetic retinopathy. This programme comprises three studies, involving a total of 4500 patients recruited from about 300 centres worldwide. The patients are normotensive or treated hypertensive individuals, and so the DIRECT programme should assess the potential of an AT(1)-receptor blocker to protect against the pathological changes in the eye following diabetes.

  14. Stimulation of the renin-angiotensin system in cats with hypertrophic cardiomyopathy.

    PubMed

    Taugner, F M

    2001-01-01

    Feline hypertrophic cardiomyopathy (HCM) is a disease of the ventricular myocardium, which may cause sudden death in cats, but neither the aetiology nor the effect on the circulation are well understood. Fourteen cats of either sex with naturally occurring HCM were studied post mortem. Their ages ranged from 9 months to 10 years with an average age of 4.9 years. Heart weights and heart weight expressed as a percentage of body weight were elevated (27.9 g and 0.65%, respectively) as compared with normal values obtained in previous studies. Myocardial disarray was evident in nine of the 14 cats and moderate to severe fibrosis was present in six animals. To evaluate the renal renin-angiotensin system, semiquantitative morphometric data were obtained by means of renin immunohistochemistry and compared with results from an earlier study of 10 healthy cats by the author. The juxtaglomerular index was 36.8% in the cats with HCM as compared with 30.6% in healthy cats. The renin-positive portion of the afferent arteriole was increased in cats affected by HCM to 86.0 microm as compared with 49.9 microm in normal cats. The increase in kidney renin values in cats with HCM may have been due to decreased blood pressure and reduced renal perfusion resulting from impaired cardiac output. PMID:11578127

  15. [Orthostatic hypotension in complicated diabetes mellitus: study of the renin-angiotensin-aldosterone system (author's transl)].

    PubMed

    Lefebvre, J; Blacker, C; Fossati, P; Linquette, M

    1979-03-01

    Plasma renin activity (P.R.A.) and plasma aldosterone (P.A.) were studied basally and after various stimuli in eight diabetic subjects with orthostatic hypotension and autonomic neuropathy. Five of them had chronic renal failure and proteinuria. On a diet containing 100 mEq Na/24 H, mean P.R.A. was 0,80 +/- 0,32 ng/ml/h in the supine position and 0,95 +/- 0,43 ng/ml/h in the upright position (N.S.); mean P.A. was 111 +/- 77 pg/ml in the supine position and 234 pg/ml in the upright position (p less than 0,01). On a diet containing 10 mEq Na/24 H, mean P.R.A. was 1,54 +/- 0,76 ng/ml/h in the supine position and 2,44 +/- 1,53 ng/ml/h in the upright position (N.S.). There was little stimulation of P. R. A. by low sodium intakes. After furosemide (n = 6), epinephrine + norepinephrine (n = 4) or diazoxide (n = 2), there was no stimulation of P.R.A. and P.A. Thus in diabetic patients with orthostatic hypotension and autonomic neuropathy basal values of P.R.A. and P.A. are in the normal range but there is dysregulation of renin-angiotensin-aldosterone system.

  16. Polymorphisms of the renin-angiotensin system genes predict progression of subclinical coronary atherosclerosis.

    PubMed

    Kretowski, Adam; McFann, Kim; Hokanson, John E; Maahs, David; Kinney, Gregory; Snell-Bergeon, Janet K; Wadwa, R Paul; Eckel, Robert H; Ogden, Lorraine; Garg, Satish; Li, Jia; Cheng, Suzanne; Erlich, Henry A; Rewers, Marian

    2007-03-01

    Premature coronary artery disease (CAD) in subjects with type 1 diabetes dramatically affects quality of life and morbidity and leads to premature death, but there is still little known about the mechanisms and predictors of this complication. In the present study, we explored the role of genetic variants of angiotensinogen (AGT, M235T), ACE (I/D), and angiotensin type 1 receptor (ATR1, A1166C) as predictors of rapid progression of subclinical coronary atherosclerosis. Five-hundred eighty-five type 1 diabetic patients and 592 similar age and sex control subjects were evaluated for progression of coronary artery calcification (CAC), a marker of subclinical CAD, before and after a 2.5-year follow-up. In logistic regression analysis, CAC progression was dramatically more likely in type 1 diabetic subjects not treated with ACE inhibitor/angiotensin receptor blocker who had the TT-ID-AA/AC genotype combination than in those with other genotypes (odds ratio 11.6 [95%CI 4.5-29.6], P < 0.0001) and was even stronger when adjusted for cardiovascular disease risk factors and the mean A1C (37.5 [3.6-388], P = 0.002). In conclusion, a combination of genotype variants of the renin-angiotensin system genes is a powerful determinant of subclinical progression of coronary artery atherosclerosis in type 1 diabetic patients and may partially explain accelerated CAD in type 1 diabetes. PMID:17327458

  17. The renin-angiotensin system and drinking in the euryhaline flounder, Platichthys flesus.

    PubMed

    Carrick, S; Balment, R J

    1983-09-01

    Drinking behaviour and its possible regulation by the renin-angiotensin system (RAS) has been examined in the euryhaline flounder. Fluid intake was greater in seawater (SW)-adapted than freshwater (FW)-adapted fish, the latter having significantly lower plasma sodium, chloride, and osmotic concentrations. Oesophageal cannulation in SW-adapted fish resulted in further elevation of drinking rates, which increased proportionally with progressive body water loss as measured by the fall in body weight and rise in plasma tonicity. The influence of the RAS on drinking in SW-adapted fish was examined in animals with an intact gastrointestinal tract. Fluid intake fell markedly following administration of the converting enzyme inhibitor, Captopril. Infusions of angiotensin I (AI) and angiotensin II (AII) induced dose-related increments in the rate of drinking. The increased drinking in response to AI was inhibited, however, by the simultaneous administration of Captopril. The results are consistent with the presence in the flounder of the major elements of the RAS, including AI, AII, and a converting enzyme-like substance. The RAS appears to play an important regulatory role in the adaptative drinking behaviour associated with migration of euryhaline teleosts between FW and SW.

  18. [Protective effect and mechanism of β-CM7 on renin angiotensin system & diabetic cardiomyopathy].

    PubMed

    Wang, Kun; Han, Dongning; Zhang, Yujuan; Rong, Chao; Zhang, Yuanshu

    2016-02-01

    This article aimed at exploring the effects and protective mechanism of β-CM7 on renin angiotensin system (RAS) in diabetic rats myocardial tissue. We divided 32 male SD rats into 4 groups: control group, diabetic model control group, insulin (3.7x10(-8) mol/d) treatment group and β-CM7 (7.5x10(-8) mol/d) treatment group. After 30 days, all rats were decapitated and myocardical tissues were collected immediately. After injection, β-CM7 could decrease the content of Ang II, increase the content of Angl-7. And β-CM7 could improve the mRNA of AT1 receptor and Mas receptor. β-CM7 also could improve the mRNA of ACE and ACE2, enhance the activity of ACE and ACE2. These data confirmed tli β-CM7 could activate ACE2-Angl-7-Mas axis, negative passage in RAS, to inhibit the expression ACE mnRiJA and protein in rat myocardium, alleviate the myocardial tissue damage induced by Ang II. The effect of β-CM7 on inhibiting myocardium damage might be related to ACE/ACE2 passageway. PMID:27382769

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

    PubMed

    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.

  20. Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro

    PubMed Central

    Caminhotto, R de O.; Sertié, R.A.L.; Andreotti, S.; Campaãa, A.B.; Lima, F.B.

    2016-01-01

    Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (−19% of maximal response and −60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (−19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients. PMID:27487419

  1. Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis

    PubMed Central

    Yang, Jie; Xiang, Fei; Cai, Peng-Cheng; Lu, Yu-Zhi; Xu, Xiao-Xiao; Yu, Fan; Li, Feng-Zhi; Greer, Peter A.; Shi, Huan-Zhong; Zhou, Qiong; Xin, Jian-Bao; Ye, Hong; Su, Yunchao

    2016-01-01

    Pleural fibrosis is defined as an excessive deposition of extracellular matrix (ECM) components that results in destruction of the normal pleural tissue architecture. It can result from diverse inflammatory conditions, especially tuberculous pleurisy. Pleural mesothelial cells (PMCs) play a pivotal role in pleural fibrosis. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodeling. However, the role of calpain in pleural fibrosis remains unknown. In the present study, we found that tuberculous pleural effusion (TPE) induced calpain activation in PMCs and that inhibition of calpain prevented TPE-induced collagen-I synthesis and cell proliferation of PMCs. Moreover, our data revealed that the levels of angiotensin (ANG)-converting enzyme (ACE) were significantly higher in pleural fluid of patients with TPE than those with malignant pleural effusion, and ACE-ANG II in TPE resulted in activation of calpain and subsequent triggering of the phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB signaling pathway in PMCs. Finally, calpain activation in PMCs and collagen depositions were confirmed in pleural biopsy specimens from patients with tuberculous pleurisy. Together, these studies demonstrated that calpain is activated by renin-angiotensin system in pleural fibrosis and mediates TPE-induced collagen-I synthesis and proliferation of PMCs via the PI3K/Akt/NF-κB signaling pathway. Calpain in PMCs might be a novel target for intervention in tuberculous pleural fibrosis. PMID:27261452

  2. Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro.

    PubMed

    Caminhotto, R de O; Sertié, R A L; Andreotti, S; Campaãa, A B; Lima, F B

    2016-07-28

    Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (-19% of maximal response and -60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (-19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients. PMID:27487419

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

    PubMed Central

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

    2016-01-01

    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. PMID:26779452

  4. Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis.

    PubMed

    Yang, Jie; Xiang, Fei; Cai, Peng-Cheng; Lu, Yu-Zhi; Xu, Xiao-Xiao; Yu, Fan; Li, Feng-Zhi; Greer, Peter A; Shi, Huan-Zhong; Zhou, Qiong; Xin, Jian-Bao; Ye, Hong; Su, Yunchao; Ma, Wan-Li

    2016-07-01

    Pleural fibrosis is defined as an excessive deposition of extracellular matrix (ECM) components that results in destruction of the normal pleural tissue architecture. It can result from diverse inflammatory conditions, especially tuberculous pleurisy. Pleural mesothelial cells (PMCs) play a pivotal role in pleural fibrosis. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodeling. However, the role of calpain in pleural fibrosis remains unknown. In the present study, we found that tuberculous pleural effusion (TPE) induced calpain activation in PMCs and that inhibition of calpain prevented TPE-induced collagen-I synthesis and cell proliferation of PMCs. Moreover, our data revealed that the levels of angiotensin (ANG)-converting enzyme (ACE) were significantly higher in pleural fluid of patients with TPE than those with malignant pleural effusion, and ACE-ANG II in TPE resulted in activation of calpain and subsequent triggering of the phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB signaling pathway in PMCs. Finally, calpain activation in PMCs and collagen depositions were confirmed in pleural biopsy specimens from patients with tuberculous pleurisy. Together, these studies demonstrated that calpain is activated by renin-angiotensin system in pleural fibrosis and mediates TPE-induced collagen-I synthesis and proliferation of PMCs via the PI3K/Akt/NF-κB signaling pathway. Calpain in PMCs might be a novel target for intervention in tuberculous pleural fibrosis. PMID:27261452

  5. Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro.

    PubMed

    Caminhotto, R de O; Sertié, R A L; Andreotti, S; Campaãa, A B; Lima, F B

    2016-07-28

    Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (-19% of maximal response and -60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (-19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients.

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

    PubMed

    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.

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

    PubMed

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

    2016-08-01

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

  8. The retinal renin-angiotensin system: implications for therapy in diabetic retinopathy.

    PubMed

    Sjølie, A K; Chaturvedi, N

    2002-08-01

    Retinopathy is the most common complication of diabetes, and a leading cause of blindness in people of working age. Optimal blood pressure and metabolic control can reduce the risk of diabetic retinopathy, but are difficult to achieve in clinical practice. In the EUCLID Study, the angiotensin converting enzyme (ACE) inhibitor lisinopril reduced the risk of progression of retinopathy by approximately 50%, and also significantly reduced the risk of progression to proliferative retinopathy. These findings are consistent with extensive evidence that the renin-angiotensin system is expressed in the eye, and that adverse effects of angiotensin II on retinal angiogenesis and function can be inhibited by ACE inhibitors or angiotensin II-receptor blockers. However, in the EUCLID Study retinopathy was not a primary end-point and the study was not sufficiently powered for the eye-related outcomes. Hence, the Diabetic Retinopathy Candesartan Trials (DIRECT) programme has been established to determine whether AT(1)-receptor blockade with candesartan can prevent the incidence and progression of diabetic retinopathy. This programme comprises three studies, involving a total of 4500 patients recruited from about 300 centres worldwide. The patients are normotensive or treated hypertensive individuals, and so the DIRECT programme should assess the potential of an AT(1)-receptor blocker to protect against the pathological changes in the eye following diabetes. PMID:12140727

  9. Prospects for Renovascular Protection by More Aggressive Renin-Angiotensin System Control

    PubMed Central

    Ruilope, Luis Miguel

    2008-01-01

    Risk factors such as hypertension or diabetes result in a continuum of renal damage. Without intervention, initial subclinical endothelial damage progresses to incipient disease, identified by microalbuminuria. Glomerular filtration rate declines, macroalbuminuria develops, and eventually end-stage renal disease (ESRD) emerges. Because of the interrelationship between cardiovascular and renal disease and their common pathophysiologies involving angiotensin II, many patients die of cardiovascular disease before renal replacement therapy is needed. Blood pressure control is key to renoprotection, but blood pressure-independent mechanisms are also implicated. Targeting the renin-angiotensin system (RAS) using angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) is a logical approach to managing all at-risk patients. In advanced nephropathy, therapy aims at retarding progression to ESRD. For incipient nephropathy, ideal therapy should bring about microalbuminuria regression. In patients at risk of renal damage, preventing early target-organ damage is essential. Although evidence of ACE inhibitor benefit is limited, data show that ARBs provide renoprotection throughout the continuum and that this may be related to their cardioprotective effects. More aggressive RAS targeting by combination blockade is under investigation. Telmisartan is an ARB that delays progression of incipient and overt diabetic nephropathy and brings about regression from microalbuminuria to normoalbuminuria in hypertensive and normotensive patients. The ultimate proof of benefit will come from the ONTARGET trial, which will evaluate the cardiovascular and renal protective effects of the combination of telmisartan and ramipril. PMID:18449382

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

    PubMed Central

    Fung, Man Lung

    2014-01-01

    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. PMID:25249981

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

    PubMed Central

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

    2016-01-01

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

  12. Associations between circulating components of the renin-angiotensin-aldosterone system and left ventricular mass.

    PubMed Central

    Schunkert, H.; Hense, H. W.; Muscholl, M.; Luchner, A.; Kürzinger, S.; Danser, A. H.; Riegger, G. A.

    1997-01-01

    OBJECTIVE: Cardiac growth may be modulated in part by the trophic effects of neurohormones. The aim of the present study was to investigate the relation between the basal activity of the renin-angiotensin-aldosterone system and left ventricular mass. DESIGN: A population based sample of 615 middle-age subjects was studied by standardised echocardiography; anthropometric measurements; and biochemical quantification of renin, pro-renin, angiotensinogen, angiotensin converting enzyme (ACE), and aldosterone. RESULTS: Echocardiographic left ventricular mass index correlated significantly with arterial blood pressure, age, and body mass index. In addition, in men ACE activity was significantly related to left ventricular mass index in univariate (P = 0.0007) and multivariate analyses (P = 0.008). Men with left ventricular hypertrophy presented with significantly higher serum ACE concentrations than those with normal left ventricular mass index (P = 0.002). In both men and women serum aldosterone was strongly related to septal and posterior wall thickness. Furthermore, in women serum aldosterone was positively and independently associated with left ventricular mass index (P = 0.0001). This effect was most prominent in hypertensive women. Finally, women with left ventricular hypertrophy presented with significantly higher serum aldosterone (P = 0.01). No significant associations with left ventricular mass index were observed for angiotensinogen, renin, or pro-renin. CONCLUSIONS: The data suggest that the variability of serum ACE or aldosterone, as occurred in this large population based sample, may contribute to the modulation of left ventricular mass. Images PMID:9038690

  13. Characterization of the renin-angiotensin system in the turtle Pseudemys scripta.

    PubMed

    Cipolle, M D; Zehr, J E

    1984-07-01

    Studies were conducted in freshwater turtles Pseudemys scripta to define some characteristics of the renin-angiotensin system in this reptile. Dialyzed acid-treated kidney extract (1 g tissue per ml water) produced a prolonged pressor response in unanesthetized turtles, which was eliminated by boiling the extract or by pretreating the turtle with [Sar1, Ile8]angiotensin II. A rat pressor assay was employed because turtle angiotensin (ANG) was bound poorly by the anti-[Asp1, Ile5, His9]ANG I used in our radioimmunoassay. Kidney extract incubated with homologous plasma (pH 5.5 and 25 degrees C) produced a time-dependent pressor response in rats. The pressor activity of the product was eliminated by dialysis or by pretreating the rats with [Sar1, Ile8]ANG II. The pressor response in anesthetized turtles to ANG I was significantly reduced by captopril, whereas the ANG II response remained unchanged, thus demonstrating the presence of ANG-converting enzyme activity in these animals. We determined the velocity of turtle ANG formation at various dilutions of enzyme (kidney extract) or substrate (plasma). Turtle kidney extract incubated with homologous plasma displayed typical Michaelis-Menten kinetics. Finally we conducted experiments to determine whether a portion of turtle plasma renin exists in an inactive form. Trypsinization caused a slight increase in plasma renin activity (PRA), whereas acidification to pH 3.3 yielded a fourfold increase in PRA.

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

    PubMed Central

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

    2015-01-01

    Dietary fats and sodium are both palatable and are hypothesized to synergistically contribute to ingestive behavior and thereby obesity. Contrary to this hypothesis, C57BL/6J mice fed a 45% high fat diet exhibited weight gain that was inhibited by increased dietary sodium content. This suppressive effect of dietary sodium upon weight gain was mediated specifically through a reduction in digestive efficiency, with no effects on food intake behavior, physical activity, or resting metabolism. Replacement of circulating angiotensin II levels reversed the effects of high dietary sodium to suppress digestive efficiency. While the AT1 receptor antagonist losartan had no effect in mice fed low sodium, the AT2 receptor antagonist PD-123,319 suppressed digestive efficiency. Correspondingly, genetic deletion of the AT2 receptor in FVB/NCrl mice resulted in suppressed digestive efficiency even on a standard chow diet. Together these data underscore the importance of digestive efficiency in the pathogenesis of obesity, and implicate dietary sodium, the renin-angiotensin system, and the AT2 receptor in the control of digestive efficiency regardless of mouse strain or macronutrient composition of the diet. These findings highlight the need for greater understanding of nutrient absorption control physiology, and prompt more uniform assessment of digestive efficiency in animal studies of energy balance. PMID:26068176

  15. Recent Update of Renin-angiotensin-aldosterone System in the Pathogenesis of Hypertension.

    PubMed

    Moon, Ju-Young

    2013-12-01

    The activation of renin-angiotensin-aldosterine system(RAAS) is one of the main pathogenesis of hypertension. All the components of RAAS are present in the kidneys at higher concentrations compared to plasma levels, and intrarenal formation of angiotensin II (Ang II) is independent of the systemic RAAS. There are some unique features in intrarenal RAAS compared to systemic RAAS. Unlike JG cells where Ang II inhibits renin release via the AngII type 1 (AT1) receptor by negative feedback, in the collecting duct Ang II stimulates renin expression via the AT1 receptor. Upregulated renin produced in the distal nephron may be able to support continued intrarenal Ang II formation leading to amplification or maintenance of the hypertensive state.The recently discovered angiotensin-converting enzyme-related carboxypeptidase 2 (ACE2)-Angiotensin-(1-7) Ang-(1-7)-Mas receptor axis has an opposing function to that of the ACE-Ang II-AT1 receptor axis.The ACE2 deficiency was associated with an increase in blood pressure, and ACE2 knockout mice have highlighted hypertensive response to Ang II infusion associated with exaggerated accumulation of Ang II in the kidney. Recently, several numbers of patients have been evaluated as the activators of ACE2-Ang-(1-7)-Mas receptor axis, which can be divided into two main classes: aimed to increase the activity of ACE2, and directed to stimulate the Ang-(1-7) receptor Mas. In order to investigate new targets for hypertension and kidney disease, further research on the function of the ACE-Ang-(1-7)-Mas receptor axis is required.

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

    PubMed

    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.

  17. Functional Local Renin-Angiotensin System in Human and Rat Periodontal Tissue

    PubMed Central

    Santos, Carlos F.; Morandini, Ana C.; Dionísio, Thiago J.; Faria, Flávio A.; Lima, Marta C.; Figueiredo, Caio M.; Colombini-Ishikiriama, Bella L.; Sipert, Carla R.; Maciel, Rubens P.; Akashi, Ana P.; Souza, Gabriela P.; Garlet, Gustavo P.; Rodini, Camila O.; Amaral, Sandra L.; Becari, Christiane; Salgado, Maria C.; Oliveira, Eduardo B.; Matus, Isaac; Didier, Daniela N.; Greene, Andrew S.

    2015-01-01

    The initiation or progression of periodontitis might involve a local renin-angiotensin system (RAS) in periodontal tissue. The aim of this study was to further characterize the local RAS in human and rat periodontal tissues between healthy and periodontally-affected tissue. Components of the RAS were investigated using in vitro, ex vivo and in vivo experiments involving both human and Wistar rat periodontium. Although not upregulated when challenged with P. gingivalis-lipopolysaccharide, human gingival and periodontal ligament fibroblasts expressed RAS components. Likewise, healthy and inflamed human gingiva expressed RAS components, some of which were shown to be functional, yet no differences in expression were found between healthy and diseased gingiva. However, in inflamed tissue the immunoreactivity was greater for the AT1R compared to AT2R in fibroblasts. When compared to healthy tissue, ACE activity was increased in human gingiva from volunteers with gingivitis. Human-gingiva homogenates generated Ang II, Ang 1-9 and Ang 1-7 when incubated with precursors. In gingiva homogenates, Ang II formation from Ang I was nearly abolished only when captopril and chymostatin were combined. Ang 1-7 formation was significantly greater when human gingiva homogenates were incubated with chymostatin alone compared to incubation without any inhibitor, only captopril, or captopril and chymostatin. In rat gingiva, RAS components were also found; their expression was not different between healthy and experimentally induced periodontitis (EP) groups. However, renin inhibition (aliskiren) and an AT1R antagonist (losartan) significantly blocked EP-alveolar-bone loss in rats. Collectively, these data are consistent with the hypothesis that a local RAS system is not only present but is also functional in both human and rat periodontal tissue. Furthermore, blocking AT1R and renin can significantly prevent periodontal bone loss induced by EP in rats. PMID:26244896

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

    NASA Technical Reports Server (NTRS)

    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.

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

    PubMed

    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.

  20. Salt appetite and the renin-angiotensin system: effect of oxytocin deficiency.

    PubMed

    Rigatto, Katya; Puryear, Robert; Bernatova, Iveta; Morris, Mariana

    2003-10-01

    To explore the role of oxytocin in the regulation of salt appetite and blood pressure, we conducted studies in oxytocin gene-knockout mice and determined (1) blood pressure and heart rate during day and night periods, (2) salt appetite after iso-osmotic volume depletion, and (3) salt appetite and blood pressure after central injection of angiotensin II. Long-term arterial catheters were inserted, and blood pressure and heart rate were recorded for 24 hours. There was a modest decrease in blood pressure and heart rate in knockout mice. Salt appetite was measured with a 2- bottle choice (water and 2% NaCl), with measurement of licking activity. Mice were injected subcutaneously with 30% polyethylene glycol (0.5 mL), and voluntary intakes were measured for 24 hours. Knockout mice consumed 3 times the amount of NaCl than did controls, 276+/-77 vs 90+/-38 licks/24 h (P<0.05). Water consumption was similar between groups. Angiotensin II (5, 50, and 200 ng/3 microL) injected intracerebroventricularly produced dose-related increases in intake, with no differences between the groups. The 50-ng dose of angiotensin II elicited salt and water intakes of 151+/-43 vs 160+/-33 licks and 250+/-53 vs and 200+/-51 licks, respectively (control vs knockout). The pressor response to angiotensin II was not different between the groups. Results suggest that oxytocin plays a role in the regulation of blood pressure and salt appetite, specifically as mediated by volume receptors, and that the renin-angiotensin system is not involved in these changes.

  1. Regulation of endothelial proliferation by the renin-angiotensin system in human umbilical vein endothelial cells.

    PubMed

    Herr, D; Rodewald, M; Fraser, H M; Hack, G; Konrad, R; Kreienberg, R; Wulff, C

    2008-07-01

    This study was performed in order to evaluate the role of angiotensin II in physiological angiogenesis. Human umbilical vein endothelial cells (HUVEC) were stained for angiotensin II type 1 receptor (AGTR1) immunocytochemically and for gene expression of renin-angiotensin system (RAS) components. The regulation of the angiogenesis-associated genes vascular endothelial growth factor (VEGF) and angiopoietins (ANGPT1 and ANGPT2) were studied using quantitative RT-PCR. Furthermore, we examined the effect of angiotensin II on the proliferation of HUVEC using Ki-67 as well as BrdU immunocytochemistry and investigated whether the administration of the AGTR1 blocker candesartan or the VEGF antagonist FLT1-Fc could suppress the observed angiotensin II-dependent proangiogenic effect. AGTR1 was expressed in HUVEC and the administration of angiotensin II significantly increased the gene expression of VEGF and decreased the gene expression of ANGPT1. Since the expression of ANGPT2 was not affected significantly the ratio of ANGPT1/ANGPT2 was decreased. In addition, a significantly increased endothelial cell proliferation was observed after stimulation with angiotensin II, which was suppressed by the simultaneous administration of candesartan or the VEGF antagonist FLT1-Fc. These results indicate the potential capacity of angiotensin II in influencing angiogenesis by the regulation of angiogenesis-associated genes via AGTR1. Since VEGF blockade opposed the effect of angiotensin II on cell proliferation, it is hypothesised that VEGF mediates the angiotensin II-dependent effect in concert with the changes in angiopoietin expression. This is the first report of the RAS on the regulation of angiogenesis-associated genes in physiology.

  2. Intrarenal renin-angiotensin system mediates fatty acid-induced ER stress in the kidney.

    PubMed

    Li, Chunling; Lin, Yu; Luo, Renfei; Chen, Shaoming; Wang, Feifei; Zheng, Peili; Levi, Moshe; Yang, Tianxin; Wang, Weidong

    2016-03-01

    Obesity-related kidney disease is related to caloric excess promoting deleterious cellular responses. Accumulation of saturated free fatty acids in tubular cells produces lipotoxicity involving significant cellular dysfunction and injury. The objectives of this study were to elucidate the role of renin-angiotensin system (RAS) activation in saturated fatty acid-induced endoplasmic reticulum (ER) stress in cultured human proximal tubule epithelial cells (HK2) and in mice fed with a high-fat diet. Treatment with saturated fatty acid palmitic acid (PA; 0.8 mM) for 24 h induced ER stress in HK2, leading to an unfolded protein response as reflected by increased expressions of the ER chaperone binding immunoglobulin protein (BiP) and proapoptotic transcription factor C/EBP homologous protein (CHOP) protein as evaluated by immunoblotting. PA treatment also induced increased protein expression of inositol requiring protein 1α (IRE1α), phosphorylated eukaryotic initiation factor-α (eIF2α), and activating transcription factor 4 (ATF4) as well as activation of caspase-3. PA treatment was associated with increased angiotensin II levels in cultured medium. The angiotensin II type 1 receptor (AT1R) blocker valsartan or renin inhibitor aliskiren dramatically suppressed PA-induced upregulation of BiP, CHOP, IRE1α, p-eIF2α, and ATF4 in HK2 cells. In contrast, valsartan or aliskiren did not prevent ER stress induced by tunicamycin. C57BL/6 mice fed with a high-fat diet for 14 wk exhibited increased protein expressions of BiP and CHOP compared with control mice, which were significantly attenuated by the valsartan treatment. Increased angiotensin II levels in serum and urine were observed in mice fed with a high-fat diet when compared with controls. It is suggested that the intrarenal RAS activation may play an important role in diabetic kidney injury via mediating ER stress induced by saturated fatty acid. PMID:26672616

  3. Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction.

    PubMed

    Zhang, W; Huang, B S; Leenen, F H

    1999-05-01

    Blockade of brain "ouabain" prevents the sympathetic hyperactivity and impairment of baroreflex function in rats with congestive heart failure (CHF). Because brain "ouabain" may act by activating the brain renin-angiotensin system (RAS), the aim of the present study was to assess whether chronic treatment with the AT1-receptor blocker losartan given centrally normalizes the sympathetic hyperactivity and impairment of baroreflex function in Wistar rats with CHF postmyocardial infarction (MI). After left coronary artery ligation (2 or 6 wk), rats received either intracerebroventricular losartan (1 mg. kg-1. day-1, CHF-Los) or vehicle (CHF-Veh) by osmotic minipumps. To assess possible peripheral effects of intracerebroventricular losartan, one set of CHF rats received the same rate of losartan subcutaneously. Sham-operated rats served as control. After 2 wk of treatment, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) at rest and in response to air-jet stress and intracerebroventricular injection of the alpha2-adrenoceptor-agonist guanabenz were measured in conscious animals. Arterial baroreflex function was evaluated by ramp changes in MAP. Compared with sham groups, CHF-Veh groups showed impaired arterial baroreflex control of HR and RSNA, increased sympathoexcitatory and pressor responses to air-jet stress, and increased sympathoinhibitory and hypotensive responses to guanabenz. The latter is consistent with decreased activity in sympathoinhibitory pathways. Chronic intracerebroventricular infusion of losartan largely normalized these abnormalities. In CHF rats, the same rate of infusion of losartan subcutaneously was ineffective. In sham-operated rats, losartan intracerebroventricularly or subcutaneously did not affect sympathetic activity. We conclude that the chronic increase in sympathoexcitation, decrease in sympathoinhibition, and desensitized baroreflex function in CHF all appear to depend on the brain RAS, since

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

    PubMed

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

    2016-06-01

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

  5. Fetal sex affects expression of renin-angiotensin system components in term human decidua.

    PubMed

    Wang, Yu; Pringle, Kirsty G; Sykes, Shane D; Marques, Francine Z; Morris, Brian J; Zakar, Tamas; Lumbers, Eugenie R

    2012-01-01

    The maternal decidua expresses the genes of the renin-angiotensin system (RAS). Human decidua was collected at term either before labor (i.e. cesarean delivery) or after spontaneous labor. The mRNA for prorenin (REN), prorenin receptor (ATP6AP2), angiotensinogen (AGT), angiotensin-converting enzymes 1 and 2 (ACE1 and ACE2), angiotensin II type 1 receptor (AGTR1), and angiotensin 1-7 receptor (MAS1) were measured by quantitative real-time RT-PCR. Decidual explants were cultured in duplicate for 24 and 48 h, and all RAS mRNA, and the secretion of prorenin, angiotensin II, and angiotensin 1-7 was measured using quantitative real-time RT-PCR, ELISA, and radioimmunoassay, respectively. In the decidua collected before labor, REN mRNA levels were higher if the fetus was female. In addition, REN, ATP6AP2, AGT, and MAS1 mRNA abundance was greater in decidual explants collected from women carrying a female fetus, as was prorenin protein. After 24 h, ACE1 mRNA was higher in the decidual explants from women with a male fetus, whereas after 48 h, both ACE1 and ACE2 mRNA was higher in decidual explants from women with a female fetus. Angiotensin II was present in all explants, but angiotensin 1-7 levels often registered below the lower limits of sensitivity for the assay. After labor, decidua, when compared with nonlaboring decidua, demonstrated lower REN expression when the fetus was female. Therefore, the maternal decidual RAS is regulated in a sex-specific manner, suggesting that it may function differently when the fetus is male than when it is female. PMID:22045662

  6. Modulation of renin angiotensin system predominantly alters sclerotic phenotype of glomeruli in HIVAN.

    PubMed

    Plagov, Andrei; Lan, Xiqian; Rai, Partab; Kumar, Dileep; Lederman, Rivka; Rehman, Shabina; Malhotra, Ashwani; Ding, Guohua; Chander, Praveen N; Singhal, Pravin C

    2014-12-01

    HIV-associated nephropathy (HIVAN) is a common complication of HIV-1 infection in patients with African ancestry in general and with APOL1 gene risk variants in particular. Although collapsing glomerulopathy is considered a hallmark of HIVAN, significant numbers of glomeruli in patients with HIVAN also display other variants of focal segmental glomerulosclerosis (FSGS). We propose that collapsed glomeruli as well as glomeruli with other variants of FSGS are manifestations of HIVAN and their prevalence depends on associated host factors. We explored the role of the renin-angiotensin system (RAS) in the manifestation of any specific glomerular phenotype in HIVAN. To evaluate the role of the RAS we have used a genetically engineered mouse model of HIVAN (Tg26) with two and four copies of angiotensinogen (Agt) gene (Tg26/Agt2 and Tg26/Agt4). In Tg26/Agt2, 1 out of 6 glomeruli exhibited sclerosed phenotype, whereas 1 out of 25 glomeruli displayed collapsed phenotype; on the other hand, in Tg26/Agt4, 1 out of 3 glomeruli exhibited sclerotic phenotype and only 1 out of 7 glomeruli showed collapsed phenotype. To inhibit the effect of RAS, Tg26/Agt2 were administered captopril, aliskiren, aliskiren plus captopril or aliskiren plus telmisartan by miniosmotic pumps for 4 weeks. In all experimental groups there was a significant reduction in percentage of sclerosed glomeruli and only minimal reduction in collapsed glomeruli compared to normal saline receiving Tg26/Agt2. These findings suggest that the manifestation of the sclerosed phenotype in HIVAN is predominantly dependent on activation of the RAS. PMID:24892944

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

    PubMed

    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.

  8. Gender differences in development of hypertension in spontaneously hypertensive rats: role of the renin-angiotensin system.

    PubMed

    Reckelhoff, J F; Zhang, H; Srivastava, K

    2000-01-01

    Previous data strongly support a role for androgens in promoting the gender difference in hypertension in the spontaneously hypertensive rat(s) (SHR), but the mechanism is not clear. Because males develop higher blood pressures than do females, we hypothesize that androgens may affect the renin-angiotensin system to promote the development of hypertension in male SHR. The present study was performed to determine the effect of converting enzyme inhibition (CEI) on the development of hypertension in SHR. Male, female, castrated male, and ovariectomized (ovx) female SHR (n=10 per gender per treatment group) received enalapril (250 mg/L) in drinking water for 8 to 10 weeks. Some ovx females were also given testosterone chronically. At 17 to 19 weeks of age, 24-hour protein excretion and mean arterial pressure were measured. By 13 weeks of age, male rats had higher systolic blood pressures by tail plethysmography than did the other rats, and CEI reduced blood pressures to similar levels in all groups. At 17 to 19 weeks, the same trend was found by direct measurement of mean arterial pressure. The ovx females treated with testosterone had serum testosterone and blood pressure levels similar to those found in males. CEI reduced mean arterial pressure to similar levels in all gender groups. Untreated males and ovx females given testosterone had significantly higher levels of urinary protein excretion than did the other groups, and CEI had no effect on proteinuria in any of the rats. These data suggest that the development of hypertension in SHR regardless of sex steroids is mediated by the renin-angiotensin system. However, the data further suggest that androgens promote the exacerbation of hypertension in male SHR via a mechanism involving the renin-angiotensin system.

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

    PubMed

    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.

  10. Characterization of a local renin-angiotensin system in rat gingival tissue

    PubMed Central

    Santos, C.F.; Akashi, A.E.; Dionísio, T.J.; Sipert, C.R.; Didier, D.N.; Greene, A.S.; Oliveira, S.H.P.; Pereira, H.J.; Becari, C.; Oliveira, E.B.; Salgado, M.C.O.

    2009-01-01

    Background Systemic renin-angiotensin system (RAS) promotes plasmatic production of angiotensin (Ang) II, which acts through interaction with specific receptors. There is growing evidence that local systems in various tissues and organs are capable of generating angiotensins independently of circulating RAS. The aims of this work were to: 1) study the expression and localization of RAS components in rat gingival tissue and 2) evaluate the in vitro production of Ang II and other peptides catalyzed by rat gingival tissue homogenates incubated with different Ang II precursors. Methods Reverse transcription-polymerase chain reaction (RT-PCR) assessed mRNA expression. Immunohistochemical (IHC) analysis aimed to detect and localize renin. Standardized fluorimetric method with tripeptide Hippuryl-Histidyl-Leucine (Hip-His-Leu) was used to measure tissue ACE activity, while high performance liquid chromatography (HLPC) showed products formed after incubation of tissue homogenates with Ang I or tetradecapeptide renin substrate (TDP). Results mRNA for renin, angiotensinogen, ACE and Ang II receptors (AT1a, AT1b and AT2) was detected in gingival tissue; cultured gingival fibroblasts expressed renin, angiotensinogen and AT1a receptor. Renin was present in the vascular endothelium and intensely expressed in the epithelial basal layer of periodontally affected gingival tissue. ACE activity was detected (4.95±0.89 nmol His-Leu/g.min). When Ang I was used as substrate, Ang 1-9 (0.576±0.128 nmol/mg.min), Ang II (0.066±0.008 nmol/mg.min) and Ang 1-7 (0.111±0.017 nmol/mg.min) were formed, whereas these same peptides (0.139±0.031; 0.206±0.046 and 0.039±0.007 nmol/mg.min, respectively) and Ang I (0.973±0.139 nmol/mg.min) were formed when TDP was the substrate. Conclusion Results presented here clearly show existence of a local RAS in rat gingival tissue, which is capable of generating Ang II and other vasoactive peptides in vitro. PMID:19228099

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

    PubMed Central

    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

  12. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system

    PubMed Central

    Li, Yan Chun; Kong, Juan; Wei, Minjie; Chen, Zhou-Feng; Liu, Shu Q.; Cao, Li-Ping

    2002-01-01

    Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor–null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] synthesis also led to an increase in renin expression, whereas 1,25(OH)2D3 injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)2D3 markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)2D3 is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension. PMID:12122115

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

    PubMed

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

    2013-02-01

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

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

    NASA Technical Reports Server (NTRS)

    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 < 0.001, low-tolerance (LoTol) group]. Mean arterial pressure (MAP) did not change measurably, but central venous pressure and left atrial diameter decreased similarly in both groups (5-6 mmHg, by approximately 30%, P < 0.05). Control (0 mmHg LBNP) hormone 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.

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

    PubMed

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

    2010-01-01

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

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

    PubMed Central

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

    2010-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    1999-01-01

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

  18. Role of Renin-Angiotensin-Aldosterone System in Metabolic Syndrome and Obesity-related Hypertension.

    PubMed

    Kamide, K

    2014-08-12

    Several recent clinical trials show that blocking agents of the renin-angiotensin-aldosterone system (RAAS) reduce cardiovascular events in patients with metabolic syndrome based on insulin resistance and obesity, especially accumulated visceral fat. Our laboratory has focused on the relationship between the vascular RAAS and the action of insulin on the vasculature. We first revealed that the addition of insulin to cultured vascular smooth muscle cells (VSMC) markedly increases angiotensinogen and angiotensin II (Ang II) expression and production. Insulin addition also induces VSMC growth that is inhibited by the blockade of the RAAS by either ACEI or ARB which suggests a role for the RAAS in insulin-mediated growth. Insulin has a quite different effect on cultured vascular endothelial cells (EC) as it reduces angiotensinogen and renin expression. However, insulin added to EC induces a marked activation of ACE and the activated ACE promotes the conversion of Ang I to Ang II and cell growth under conditions of high insulin concentration. Ang II induces the progression of atherosclerosis through the production of oxidative stress that blocks insulin signaling and accelerates atherosclerosis. In this paper, we attempt to clarify the relationship between insulin resistance, the RAAS, and oxidative stress in vascular tissues to mimic in vivo conditions found in patients with metabolic syndrome and obesity-related hypertension as previously I reviewed in "Current Hypertension Reviews" in 2010 [1]. In addition, I update the relationships between vascular RAAS and insulin resistance for the last 4 years. JSH-2014 [2] states that the target goals of blood pressure (BP) for diabetes patients is lower than 130/80 mmHg, whereas updated JNC 8 [3] and ESH-ESC 2013 [4] recommends the target BP was changed to <140/90 mmHg for hypertensive patients with diabetes. Patients with diabetes and hypertension have reduced mortality as well as improved cardiovascular and cerebrovascular

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

    PubMed

    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.

  20. [The renin-angiotensin-aldosterone system during the extraction, concentration and reinfusion of ascitic fluid in cirrhotic patients].

    PubMed

    Giorcelli, V; Fossale, P G

    1983-01-01

    The course of hepatic cirrhosis involves alterations to the sodium-water balance, the aetiopathogenetic causes of which are still not entirely known. At first major importance was assigned to the role of secondary hyperaldosteronism which develops during the ascitic phase. This was subsequently recognised to have only a permissive rather than determinant function. Changes in the renin-angiotensin-aldosterone (RAA) system and variations in hydrosaline balance as the extracellular volume (ECV) expands during the reinfusion of concentrated ascitic fluid have been studied. The data reported show that ECV expansion causes increased diuresis, natriuresis and osmolar clearance. The RAA system is suppressed and at the same time kaliuresis increases. The latter factor points up the role played by increased solute flow to the distal tube in the diuretico-metabolic response, where aldosterone plays a purely permissive part. PMID:6675585

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

    PubMed

    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.

  2. The renin-angiotensin system and advanced glycation end-products in diabetic retinopathy: impacts and synergies.

    PubMed

    Miller, Antonia G; Zhu, Tong; Wilkinson-Berka, Jennifer L

    2013-11-01

    Diabetic retinopathy is a major cause of vision impairment and blindness and represents a significant health burden throughout the world. There is considerable interest in developing new treatments that retard the progression of diabetic retinopathy from its early to proliferative stages. It could be argued that the absence of an ideal therapy for diabetic retinopathy comes from an incomplete understanding about the biochemical mechanisms that underlie this disease, and their precise impact on specific retinal cell populations. Findings from pre-clinical and clinical studies indicate that both the renin-angiotensin system (RAS) and advanced glycation end-products (AGEs) influence various aspects of diabetic retinopathy. Of interest is growing evidence of cross-talk between the RAS and AGEs pathways. This review will discuss the role of both the RAS and AGEs in diabetic retinopathy, and how the identification of interactions between the two pathways may have implications for the development of new treatment strategies. PMID:23173957

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

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

    2016-01-01

    KCNQ1 (KvLQT1) is the pore-forming a-subunit of the potassium channel. To uncover its role in electrolyte metabolism, we investigated the effects of KCNQ1 A340E, a loss-of-function mutant, on J343 mice. Compared with the normal controls (C57BL/6J mice) bearing the wild-type KCNQ1 gene, J343 mice bearing KCNQ1 A340E demonstrated a much higher 24-h intake of electrolytes (potassium, sodium, and chloride). However, they suffered from significant electrolyte loss through both the feces and urine during a period of 24 h. Unbalance in electrolyte metabolism disrupted the electrolyte homeostasis in the J343 mice, which was characterized by the comparatively lower level of serum potassium (J343 vs C57BL/6J: 12.06 ± 1.47 vs 14.44 ± 3.58 mM, P = 0.01) and higher levels of serum sodium (J343 vs C57BL/6J: 148.05 ± 4.47 vs 115.15 ± 17.25 mM, P = 4.20 x 10(-4)) and chloride (J343 vs C57BL/6J: 118.0 ± 4.47 vs 85.21 ± 11.90 mM, P = 2.47 x 10(-5)). Between the J343 and C57BL/6J mice, there was no statistically significant difference in KCNQ1 expression in the gastrointestinal tract and kidney. Normal concentrations of plasma renin, angiotensin I, and aldosterone were also detected in both lines of mice. KCNQ1, therefore, is suggested to play a central role in electrolyte metabolism. KCNQ1 A340E, with the loss-of-function phenotype, may dysregulate electrolyte homeostasis in mice independently of the activity of the renin-angiotensin-aldosterone system. PMID:27525866

  8. Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation.

    PubMed

    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.

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

    PubMed

    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. Fructose-Rich Diet-Induced Changes in the Expression of the Renin Angiotensin System Molecules in the Heart of Ovariectomized Female Rats Could be Reversed by Estradiol.

    PubMed

    Bundalo, M; Zivkovic, M; Tepavcevic, S; Culafic, T; Koricanac, G; Stankovic, A

    2015-06-01

    The renin-angiotensin system has been implicated in the development of metabolic syndrome and appears to be a key in the local tissue control of normal cardiac functions. Physiological concentrations of estrogens have been shown to be cardioprotective, especially against the damaging effects of fructose-rich diet. The aim of the study was to investigate the expression of the renin-angiotensin system molecules with potentially deleterious effect on the heart (angiotensin-converting enzyme and angiotensin II type 1 receptor) and those with potentially protective effects, (angiotensin-converting enzyme 2 and angiotensin II type 2 receptor), in ovariectomized fructose fed female rats with 17β-estradiol replacement. Real-time PCR and Western blot analysis were used for quantification of gene and protein expression in the heart. Fructose diet increased the expression of angiotensin-converting enzyme and angiotensin II type 1 receptor and decreased the expression of angiotensin-converting enzyme 2 and angiotensin II type 2 receptor. On the other hand, estradiol replacement seems to undo fructose diet effects on cardiac renin-angiotensin system. Downregulation of angiotensin-converting enzyme and angiotensin II type 1 receptor, and reversion of expression of both potentially protective molecules, angiotensin-converting enzyme 2 and angiotensin II type 2 receptor, to the control level in cardiac tissue took place. Obtained results suggest that estradiol may reverse the harmful effect of fructose-rich diet on the expression of renin-angiotensin system molecules. These findings may also be important in further research of phenotypes like insulin resistance, metabolic syndrome, and following cardiovascular pathology in females.

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

    PubMed Central

    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

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

    PubMed

    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.

    PubMed

    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.

    PubMed

    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

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

    NASA Technical Reports Server (NTRS)

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

    PubMed

    Naffah-Mazzacoratti, Maria da Graça; Gouveia, Telma Luciana Furtado; Simões, Priscila Santos Rodrigues; Perosa, Sandra Regina

    2014-05-26

    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. PMID:24921004

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

    PubMed Central

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

    2015-01-01

    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. PMID:26084692

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

    PubMed

    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.

  19. Obesity induces neuroinflammation mediated by altered expression of the renin-angiotensin system in mouse forebrain nuclei.

    PubMed

    de Kloet, Annette D; Pioquinto, David J; Nguyen, Dan; Wang, Lei; Smith, Justin A; Hiller, Helmut; Sumners, Colin

    2014-09-01

    Obesity is a widespread health concern that is associated with an increased prevalence of hypertension and cardiovascular disease. Both obesity and hypertension have independently been associated with increased levels of inflammatory cytokines and immune cells within specific brain regions, as well as increased activity of the renin-angiotensin system (RAS). To test the hypothesis that high-fat diet (HFD) induced obesity leads to an angiotensin-II (Ang-II)-dependent increase in inflammatory cells within specific forebrain regions that are important for cardiovascular regulation, we first assessed microglial activation, astrocyte activation, inflammation and RAS component gene expression within selected metabolic and cardiovascular control centers of the forebrain in adult male C57BL/6 mice given either a HFD or a low-fat diet (LFD) for 8weeks. Subsequently, we assessed the necessity of the paraventricular nucleus of the hypothalamus (PVN) angiotensin type-1a (AT1a) receptor for these responses by using the Cre/lox system in mice to selectively delete the AT1a receptor from the PVN. These studies reveal that in addition to the arcuate nucleus of the hypothalamus (ARC), the PVN and the subfornical organ (SFO), two brain regions that are known to regulate blood pressure and energy balance, also initiate proinflammatory responses after the consumption of a diet high in fat. They further indicate that some, but not all, of these responses are reversed upon deletion of AT1a specifically within the PVN.

  20. Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ.

    PubMed

    Coble, Jeffrey P; Grobe, Justin L; Johnson, Alan Kim; Sigmund, Curt D

    2015-02-15

    It is critical for cells to maintain a homeostatic balance of water and electrolytes because disturbances can disrupt cellular function, which can lead to profound effects on the physiology of an organism. Dehydration can be classified as either intra- or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin-angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra- and extracellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptors (AT2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the mitogen-activated protein (MAP) kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the subfornical organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and ANG II.

  1. The Beneficial Effect of Renin-Angiotensin-Aldosterone System Blockade in Marfan Syndrome Patients after Aortic Root Replacement

    PubMed Central

    Lee, Seung-Jun; Oh, Jaewon; Ko, Young-Guk; Lee, Sak; Chang, Byung-Chul; Lee, Do Yun; Kwak, Young-Ran

    2016-01-01

    Purpose In this study, we evaluated the long term beneficial effect of Renin-Angiotensin-Aldosterone System (RAAS) blockade therapy in treatment of Marfan aortopathy. Materials and Methods We reviewed Marfan syndrome (MFS) patients who underwent aortic root replacement (ARR) between January 1996 and January 2011. All patients were prescribed β-blockers indefinitely. We compared major aortic events including mortality, aortic dissection, and reoperation in patients without RAAS blockade (group 1, n=27) to those with (group 2, n=63). The aortic growth rate was calculated by dividing the diameter change on CT scans taken immediately post-operatively and the latest scan available. Results There were no differences in clinical parameters except for age which was higher in patients with RAAS blockade. In group 1, 2 (7%) deaths, 5 (19%) aortic dissections, and 7 (26%) reoperations occurred. In group 2, 3 (5%) deaths, 2 (3%) aortic dissections, and 3 (5%) reoperations occurred. A Kaplan-Meier plot demonstrated improved survival free from major aortic events in group 2. On multivariate Cox, RAAS blockade was an independent negative predictor of major aortic events (hazard ratio 0.38, 95% confidence interval 0.30-0.43, p=0.002). Mean diameter change in descending thoracic and supra-renal abdominal aorta was significantly higher in patients without RAAS blockade (p<0.05). Conclusion In MFS patients who underwent ARR, the addition of RAAS blockade to β-blocker was associated with reduction of aortic dilatation and clinical events. PMID:26632386

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

    PubMed Central

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

    2015-01-01

    Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective effect. Thus, we investigated localized cardiac angiotensin II type I and type II receptors (AT1R, AT2R), downstream effectors, and phenotypic outcomes using mouse models of the combination of aging and inflammation and compared it to a model of aging and a model of inflammation. We show molecular distinction in the combined effect of aging and inflammation as compared to each independently. The combination maintained an increased AT1R:AT2R and expression of Nox2 and exhibited the lowest activity of antioxidants. Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy. These phenotypic similarities have dubbed inflammatory conditions as premature aging, but they are, in fact, molecularly distinct. Moreover, treatment with an AT1R blocker, losartan, selectively reversed the signaling changes and ameliorated adverse phenotypic effects in the combination of aging and inflammation as well as each independently. PMID:26221650

  3. Trientine and renin-angiotensin system blockade ameliorate progression of glomerular morphology in hypertensive experimental diabetic nephropathy.

    PubMed

    Moya-Olano, Leire; Milne, Helen Marie; Robinson, Jillian Margaret; Hill, Jonathan Vernon; Frampton, Christopher Miles; Abbott, Helen Frances; Turner, Rufus; Kettle, Anthony James; Endre, Zoltán Huba

    2011-11-01

    A comparison of the efficacy of the copper chelator, trientine, with combined renin angiotensin system (RAS) blockade on the progression of glomerular pathology in the diabetic (mREN-2)27 rat is reported. Animals were treated for 2 months with trientine, combined RAS blockers, combined trientine plus RAS blockers or none. Treatments began after inducing diabetes with streptozotocin. Physiological data were recorded monthly and light microscopic glomerular features were scored. Plasma allantoin and both plasma and renal protein carbonyls were measured as markers of oxidative stress. Trientine and RAS blockade decreased proteinuria and albuminuria and prevented an increase in creatinine clearance and kidney weight. Both reduced the diabetes-related glomerular features of mesangiolysis and glomerular segmental hypocellularity and trientine prevented severe tuft-to-capsule adhesion and reduced tubularization. Hypertension-related severe mesangial matrix expansion and global hypercellularity were increased by both treatments, which may reflect repair of mesangiolysis. Trientine reduced plasma but not renal protein carbonyls or plasma allantoin. In this model, trientine prevented the development of many diabetes-specific features similarly to RAS blockade. Amelioration of oxidative stress and features commonly observed in human diabetic nephropathy (DN), support a diabetes-related defect in copper (Cu) metabolism. The addition of Cu(II) chelation may improve current DN therapy.

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

    PubMed

    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.

  5. Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients.

    PubMed

    Bantle, J P; Nath, K A; Sutherland, D E; Najarian, J S; Ferris, T F

    1985-03-01

    To evaluate the mechanism of cyclosporine-induced hyperkalemia, the renin-angiotensin-aldosterone system and renal potassium clearance were compared in ten renal transplant recipients treated with cyclosporine and treated with azathioprine. After stimulation by a low-sodium diet and furosemide, cyclosporine-treated patients demonstrated lower plasma renin activity when supine (1.9 +/- 0.3 v 7.8 +/- 1.4 ng/mL/hr) and after standing (3.0 +/- 0.7 v 12.2 +/- 1.5 ng/mL/hr). Supine plasma aldosterone levels tended to be lower in cyclosporine-treated patients, (4.8 +/- v 10.5 +/- 2.6 ng/dL), although standing plasma aldosterone levels were not different (10.8 +/- 3.0 v 12.3 +/- 2.0 ng/dL). After administration of 0.75 mEq of potassium chloride per kilogram of body weight, cyclosporine-treated patients excreted 52% +/- 7.1% of the potassium load in six hours compared with excretion of 67% +/- 7.0% by the azathioprine-treated patients, although there was no difference in plasma aldosterone levels in response to the potassium load in the two groups. These data suggest that cyclosporine causes suppression of plasma renin activity and a tubular insensitivity to aldosterone, both of which may impair potassium excretion.

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

    PubMed

    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

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

    PubMed

    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

    2016-09-21

    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.

  8. [Alterations of calcium, magnesium, and zinc in essential hypertension:their relation to the renin-angiotensin-aldosterone system].

    PubMed

    García Zozaya, J L; Padilla Viloria, M

    1997-11-01

    Based on our studies at the Hypertension research unit, we have found that the renin-angiotensin aldosterone. System (RAAS) undergoes several changes being the following the most relevant: Low plasma renin concentration (LPRC), while the plasma Aldosterone concentration is high (HPAC). At the same time we found calcium metabolism alterations: High urine calcium excretion, low serum ionic calcium and high PTH level. This alterations are more evident if the elder patient become hypertensive. We have found this changes in several groups in our community: black, ancient, obese and diabetic patients; who more often suffer hypertension and they must be followed up closely. In this group there are the sodium dependent hypertensive and they are the one who can get beneficial effects from the low salt diet and high calcium intake. When we studied the low plasma renin hypertensive we found the calcium changes mentioned before in ancient patient, as well as, high urine Zinc excretion. When we gave and oral calcium supplement to these patients, we saw that the calcium and Zinc alterations mentioned before were corrected. The high plasma renin concentration hypertensive patients showed low serum magnesium concentration and high urine magnesium excretion. A brief comment on the possible role of oxidative stress on essential hypertension is made. PMID:9471228

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

    PubMed Central

    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

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

    PubMed

    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.

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

    PubMed

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

    PubMed

    Henriksen, Erik J; Prasannarong, Mujalin

    2013-09-25

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

  13. H2S Inhibits Hyperglycemia-Induced Intrarenal Renin-Angiotensin System Activation via Attenuation of Reactive Oxygen Species Generation

    PubMed Central

    Ni, Jun; Li, Chen; Shao, Decui; Liu, Jia; Shen, Yang; Wang, Zhen; Zhou, Li; Zhang, Wei; Huang, Yu; Yu, Chen; Wang, Rui; Lu, Limin

    2013-01-01

    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. PMID:24058553

  14. A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology.

    PubMed

    Balakumar, Pitchai; Jagadeesh, Gowraganahalli

    2014-10-01

    Ang II, the primary effector pleiotropic hormone of the renin-angiotensin system (RAS) cascade, mediates physiological control of blood pressure and electrolyte balance through its action on vascular tone, aldosterone secretion, renal sodium absorption, water intake, sympathetic activity and vasopressin release. It affects the function of most of the organs far beyond blood pressure control including heart, blood vessels, kidney and brain, thus, causing both beneficial and deleterious effects. However, the protective axis of the RAS composed of ACE2, Ang (1-7), alamandine, and Mas and MargD receptors might oppose some harmful effects of Ang II and might promote beneficial cardiovascular effects. Newly identified RAS family peptides, Ang A and angioprotectin, further extend the complexities in understanding the cardiovascular physiopathology of RAS. Most of the diverse actions of Ang II are mediated by AT1 receptors, which couple to classical Gq/11 protein and activate multiple downstream signals, including PKC, ERK1/2, Raf, tyrosine kinases, receptor tyrosine kinases (EGFR, PDGF, insulin receptor), nuclear factor κB and reactive oxygen species (ROS). Receptor activation via G12/13 stimulates Rho-kinase, which causes vascular contraction and hypertrophy. The AT1 receptor activation also stimulates G protein-independent signaling pathways such as β-arrestin-mediated MAPK activation and Src-JAK/STAT. AT1 receptor-mediated activation of NADPH oxidase releases ROS, resulting in the activation of pro-inflammatory transcription factors and stimulation of small G proteins such as Ras, Rac and RhoA. The components of the RAS and the major Ang II-induced signaling cascades of AT1 receptors are reviewed.

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

    PubMed

    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.

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

    PubMed

    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.

  17. The Effect of Renin-angiotensin System Inhibitors on Kidney Allograft Survival: A Systematic Review and Meta-analysis

    PubMed Central

    Cheungpasitporn, Wisit; Thongprayoon, Charat; Mao, Michael A.; Kittanamongkolchai, Wonngarm; Sathick, Insara J. J.; Erickson, Stephen B.

    2016-01-01

    Background: The use of renin-angiotensin system (RAS) inhibitors in patients with chronic kidney disease, and especially in diabetic kidney disease, has been shown to provide renoprotective effects and slow progression to end-stage renal disease. However, this protective effect in kidney transplant patient populations is unclear. Aim: The objective of this systematic review and meta-analysis was to evaluate the effect of RAS inhibitors on kidney allograft survival. Materials and Methods: A literature search for randomized controlled trials (RCTs) was performed from inception through February 2016. Studies that reported relative risks or hazard ratios comparing the risks of renal graft loss in renal transplant recipients who received RAS inhibitors vs. controls were included. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effect, generic inverse variance method. Results: Five studies (3 RCTs and 2 cohort studies) with 20024 kidney transplant patients were included in the meta-analysis. Pooled RR of allograft failure in recipients who received RAS inhibitors was 0.73 (95% CI: 0.45–1.21). When meta-analysis was limited only to RCTs, the pooled RR of allograft failure in patients using RAS inhibitors was 0.59 (95%: CI 0.20–1.69). The risk for mortality (RR: 1.13 [95% CI: 0.62–2.07]) in patients using RAS inhibitors compared to controls was not significantly reduced. Conclusion: This meta-analysis demonstrated insignificant reduced risks of renal graft loss among renal transplant recipients who received RAS inhibitors. Future studies assessing the potential benefits of RAS inhibitors on allograft survival in specific kidney transplant patient populations are needed. PMID:27583237

  18. Concomitant inhibition of renin angiotensin system and Toll-like receptor 2 attenuates renal injury in unilateral ureteral obstructed mice

    PubMed Central

    Chung, Sarah; Jeong, Jin Young; Chang, Yoon Kyung; Choi, Dae Eun; Na, Ki Ryang; Lim, Beom Jin; Lee, Kang Wook

    2016-01-01

    Background/Aims: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. Methods: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. Results: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor β (TGF-β) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-β in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. Conclusions: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney. PMID:26932402

  19. Targeting the renin-angiotensin system combined with an antioxidant is highly effective in mitigating radiation-induced lung damage

    PubMed Central

    Mahmood, Javed; Jelveh, Salomeh; Zaidi, Asif; Doctrow, Susan R.; Medhora, Meetha; Hill, Richard P.

    2014-01-01

    Purpose We investigated the outcome of suppression of renin angiotensin system (RAS) using Captopril combined with an antioxidant (EUKarion-207) for mitigation of radiation-induced lung damage in rats. Materials and Methods The thoracic cavity of female Sprague-Dawley (SD) rats was irradiated with single dose of 11 Gy. Treatment with Captopril at a dose of 40 mg/kg/day in drinking water and EUK-207 given by subcutaneous injection (8 mg/kg daily) was started 1 week (wk) post-irradiation (PI) and continuing until 14 wks PI. Breathing rate was monitored until the rats were sacrificed at 32 wks PI when lung fibrosis was assessed by lung hydroxyproline content. Lung levels of the cytokine, Transforming Growth Factor (TGF)-β1, and macrophage activation were analyzed by immunohistochemistry. Oxidative DNA damage was assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG) levels and lipid peroxidation was measured by a T-BARS assay. Results The increase in breathing rate in the irradiated rats was significantly reduced by the drug treatments. The drug treatment also significantly decreased the hydroxyproline content, 8-OHdG and malondialdehyde levels, and levels of activated macrophages and the cytokine TGF-β1 at 32 wks. Almost complete mitigation of these radiation effects was observed by combining Captopril and EUK-207. Conclusion Captopril and EUK-207 can provide mitigation of radiation-induced lung damage out to at least 32 wks PI following treatment given 1–14 wks PI. Overall the combination of Captopril and EUK-207 was more effective than the individual drugs used alone. PMID:24867538

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

    PubMed

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

    2007-03-01

    Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thereby risk for arterial thrombosis. Activation of the renin-angiotensin system has been linked to the production of PAI-1 expression via the angiotensin II type 1 receptor (AT1R). In addition, bradykinin can induce the release of t-PA through a B2 receptor mechanism. In the present study, we aimed to investigate the epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels in a large population-based sample (n=2527). We demonstrated a strong significant interaction within genetic variations of the bradykinin B2 gene (P=0.002) and between ACE and bradykinin B2 (p=0.003) polymorphisms on t-PA levels in females. In males, polymorphisms in the bradykinin B2 and AT1R gene showed the most strong effect on t-PA levels (P=0.006). In both females and males, the bradykinin B2 gene interacted with AT1R gene on plasma PAI-1 levels (P=0.026 and P=0.039, respectively). In addition, the current study found a borderline significant interaction between PAI 4G5G and ACE I/D on plasma t-PA and PAI-1 levels. These results support the idea that the interplay between the renin-angiotensin, bradykinin, and fibrinolytic systems might play an important role in t-PA and PAI-1 biology.

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

    PubMed

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

    2016-09-01

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

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

    PubMed

    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.

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

    PubMed

    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. Plasma Molecular Signatures in Hypertensive Patients With Renin-Angiotensin System Suppression: New Predictors of Renal Damage and De Novo Albuminuria Indicators.

    PubMed

    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. PMID:27217411

  5. Plasma Molecular Signatures in Hypertensive Patients With Renin-Angiotensin System Suppression: New Predictors of Renal Damage and De Novo Albuminuria Indicators.

    PubMed

    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.

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

    PubMed

    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. PMID:27375489

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

    PubMed

    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.

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

    PubMed Central

    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. PMID:27375489

  9. Pharmacologic inhibition of the renin-angiotensin system did not attenuate hepatic toxicity induced by carbon tetrachloride in rats.

    PubMed

    Ekor, Martins; Odewabi, Adesina O; Kale, Oluwafemi E; Oritogun, Kolawole S; Adesanoye, Omolola A; Bamidele, Titilayo O

    2011-11-01

    The renin-angiotensin system (RAS) subserves vital physiological functions and also implicated in certain pathological states. Modulation of this system has been proposed in recent studies to be a promising strategy in treating liver fibrosis. We investigated the effect of the pharmacologic inhibition of RAS with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in CCl(4)-induced liver injury with a view to ascertaining the chemopreventive benefit. Fifty-six Wistar albino rats were divided into eight experimental groups of seven rats/group. Groups 1-4 received normal saline (10 ml/kg), enalapril (0.6 mg/kg), losartan (1.4 mg/kg) and CCl(4) (80 mg/kg), respectively. Groups 5-8 were pretreated with enalapril (0.3 mg/kg), enalapril (0.6 mg/kg), losartan (0.7 mg/kg) and losartan (1.4 mg/kg) 1 hour before CCl(4) administration. Experiment lasted 11 days and dosing was via oral route. Rats were killed 24 hours after the last treatment. Serum activities of alkaline phosphatase, aspartate and alanine aminotransferases increased significantly (p < 0.05) by 46.0%, 90.6% and 122.3%, respectively, with severe hepatic centrilobular necrosis, fatty infiltration and increase in liver weight (p < 0.05) in the CCl(4)-treated rats. Enalapril (0.6 mg/kg) and losartan (1.4 mg/kg) significantly (p < 0.05) increased aspartate aminotransferase activity by 37.0% and 94.7% and produced mild centrilobular and periportal hepatic necrosis, respectively, with enalapril significantly (p < 0.05) increasing liver weight. Serum total cholesterol, triglyceride, albumin and total protein did not change significantly in these rats. Also, glutathione, malondialdehyde and uric acid levels were not significantly altered. Enalapril and losartan failed to attenuate liver injury associated with CCl(4) treatment. Although both drugs did not significantly alter serum biochemistry in the CCl(4)-treated rats, they however produced slight elevations in biomarkers of liver function and

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

    PubMed

    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.

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

    PubMed

    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.

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

    NASA Technical Reports Server (NTRS)

    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

  13. Inflammatory markers in paroxysmal atrial fibrillation and the protective role of renin-angiotensin-aldosterone system inhibitors

    PubMed Central

    ROŞIANU, ŞTEFAN HORIA; ROŞIANU, ADELA-NICOLETA; ALDICA, MIHAI; CĂPÂLNEANU, RADU; BUZOIANU, ANCA DANA

    2013-01-01

    Background Experimental and clinical studies have shown the importance of inflammation in the pathophysiology of atrial fibrillation (AF). The renin-angiotensin-aldosterone system (RAAS) may play an important role in the pathogenesis of AF in correlation with the inflammatory process. RAAS inhibition may have important therapeutic value in limiting AF. The aim of this study was the correlation between inflammatory markers and recurrent episodes of AF in patients with known paroxysmal atrial fibrillation, with and without treatment with RAAS inhibitors. Methods and results We studied 82 patients with paroxysmal AF recorded at “Niculae Stancioiu” Heart Institute Cluj-Napoca, divided into two groups: group A treated with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) and group B without this medication. All patients underwent clinical examination, ECG, echocardiography and determination of plasma levels of inflammatory markers represented by high sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6). In the group treated with ACE inhibitors/ARBs, AF burden was significantly lower than in patients without treatment. We obtained a strong positive correlation between blood levels of high-sensitivity CRP and those of IL-6 (r=0.64, p<0.001), the number of yearly AF episodes (r=0.570, p<0.001), LA diameter (r=0.5, p<0.001) and LA volume (r=0.5, p<0.001). We found moderate positive correlations between blood levels of IL-6 and LA diameter (r=0.305, p=0.01), LA volume (r=0.314, p=0.01), the number of yearly AF episodes (r=0.489, p<0.001), the total number of AF episodes (r=0.304, p<0.001), BMI (r=0.473, p<0.001), LA area (r=0.458, p<0.001), LA area index (r=0.334, p=0.007) and LA volume index (r=0.304, p=0.01). The number of yearly AF episodes and BMI values influenced IL-6 blood levels (t=3.46, p=0.001, respectively t=2.17, p=0.03). Conclusions Inflammation is present in patients with AF, with or without treatment with

  14. BR 09-2 NOVEL APPROACHES TO THE RENIN ANGIOTENSIN SYSTEM IN PROTEINURIC KIDENY DISEASE.

    PubMed

    Scholey, James

    2016-09-01

    The classical view of the RAS is a linear signaling pathway beginning with the conversion of angiotensinogen to ANG I by renin, an enzyme secreted by the kidney. ANG I is converted to ANG II by angiotensin converting enzyme (ACE) ANG II binds to the G-protein coupled angiotensin II receptor type 1. The RAS is a circulating system but we now know that the RAS is also locally expressed in a number of tissues, including the kidneys and the heart. ANG II exerts adverse hemodynamic and non-hemodynamic effects on renal cells. The hemodynamic effects include: systemic vasoconstriction and increases in glomerular capillary pressur. The non-hemodynamic effects include: stimulation of proximal sodium re-absorption, stimulation of gluconeogenesis and ammoniagenesis, growth factor release, stimulation of extracellular matrix production, inflammatory cytokine release, and monocyte/macrophage migration. ANG II also induces epithelial-mesenchymal transition. ANG II can also be processed by enzymes with important implications for kidney injury. The recent discovery and characterization of a homolog for ACE, ACE2, builds on this emerging theme of complexity. ACE2 expression is highest in the heart, kidney, and the vascular endothelium. ACE2 differs importantly from that of ACE. ACE hydrolyzes ANG I to ANG II while ACE2 hydrolyzes ANG II to ANG 1-7. Accordingly, ACE2 is predicted to reduce tissue ANG II and increase ANG 1-7. I will describe our work treatment with ACE2 in an experimental model of proteinuric kidney disease which we think will shift the paradigm for management of proteinuria in glomerular diseases which currently emphasizes RAS blockade. PMID:27643290

  15. Study of the rat adrenal renin-angiotensin system at a cellular level.

    PubMed Central

    Chiou, C Y; Williams, G H; Kifor, I

    1995-01-01

    To address the question as to how zona glomerulosa (ZG) cell angiotensin II (Ang II) secretion is regulated, we developed an immuno-cell blot assay to measure its secretion from single cells. We compared these results with those obtained from population studies using a superfusion system. Modulation of Ang II secretion was investigated acutely (by administrating potassium [K+] or captopril) and chronically (by feeding the animals low or high sodium diets). The area of secretory cells, halo areas, and halo intensities varied widely but were highly significantly correlated (P < 0.001) with each other. A disproportionate amount of Ang II was secreted by a small number of large cells. When K+ concentration was increased from 3.6 to 0 mM, superfused ZG cells increased their Ang II secretion 2.32 +/- 0.59-fold. Administration of captopril reduced the K(+)-stimulated Ang II secretion 1.24 +/- 0.07 fold. These findings were reflected in the cell blot assay as a change in the frequency distribution of halo area by K+ and captopril in the same direction as in the population study. In both conditions, the percentage of secretory cells did not change significantly from control. Superfused ZG cells from rats on a low sodium diet secreted 1.85 +/- 0.58-fold more Ang II than cells from sodium-loaded rats (p < 0.05, n = 6). The cell blot assay confirmed these findings with sodium restriction significantly increasing (P < 0.001) both the halo area and its frequency distribution to a larger portion of high secreting cells. However, in contrast to acute treatment with K+ or captopril, the number of secretory cells also doubled. Thus, the individual ZG cell uses two mechanisms to modify Ang II production. In response to acute stimulation and suppression, the amount of Ang II secreted per cell is modified without changing the number of secretary cells. With chronic stimulation, both the amount of Ang II secreted per cell and the number of secretary cells increase. Images PMID:7657812

  16. Statins and Renin Angiotensin System Inhibitors Dose-Dependently Protect Hypertensive Patients against Dialysis Risk

    PubMed Central

    Wu, Szu-Yuan

    2016-01-01

    Background Taiwan has the highest renal disease incidence and prevalence in the world. We evaluated the association of statin and renin–angiotensin system inhibitor (RASI) use with dialysis risk in hypertensive patients. Methods Of 248,797 patients who received a hypertension diagnosis in Taiwan during 2001–2012, our cohort contained 110,829 hypertensive patients: 44,764 who used RASIs alone; 7,606 who used statins alone; 27,836 who used both RASIs and statins; and 33,716 who used neither RASIs or statins. We adjusted for the following factors to reduce selection bias by using propensity scores (PSs): age; sex; comorbidities; urbanization level; monthly income; and use of nonstatin lipid-lowering drugs, metformin, aspirin, antihypertensives, diuretics, and beta and calcium channel blockers. The statin and RASI use index dates were considered the hypertension confirmation dates. To examine the dose–response relationship, we categorized only statin or RASI use into four groups in each cohort: <28 (nonusers), 28–90, 91–365, and >365 cumulative defined daily doses (cDDDs). Results In the main model, PS-adjusted hazard ratios (aHRs; 95% confidence intervals [CIs]) for dialysis risk were 0.57 (0.50–0.65), 0.72 (0.53–0.98), and 0.47 (0.41–0.54) in the only RASI, only statin, and RASI + statin users, respectively. RASIs dose-dependently reduced dialysis risk in most subgroups and in the main model. RASI use significantly reduced dialysis risk in most subgroups, regardless of comorbidities or other drug use (P < 0.001). Statins at >365 cDDDs protected hypertensive patients against dialysis risk in the main model (aHR = 0.62, 95% CI: 0.54–0.71), regardless of whether a high cDDD of RASIs, metformin, or aspirin was used. Conclusion Statins and RASIs independently have a significant dose-dependent protective effect against dialysis risk in hypertensive patients. The combination of statins and RASIs can additively protect hypertensive patients against dialysis

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

    PubMed

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

    2003-06-20

    Local renin-angiotensin systems (RAS) have been postulated in brain, pituitary and adrenal glands. These local RAS have been implicated, respectively, in the central regulation of the cardiovascular system and body water balance, the secretion of pituitary hormones and the secretion of aldosterone by adrenal glands. By other hand, it is known that the hypothalamus-pituitary-adrenal (HPA) axis is involved in blood pressure regulation, and is affected by sex hormones. The aim of the present work is to analyze the influence of testosterone on RAS-regulating aminopeptidase A, B and M activities and vasopressin-degrading activity in the HPA axis, measuring these activities in their soluble and membrane-bound forms in the hypothalamus, pituitary and adrenal glands of orchidectomized males and orchidectomized males treated subcutaneously with several doses of testosterone. The present data suggest that in male mice, testosterone influences the RAS- and vasopressin-degrading activities at all levels of the HPA axis.

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

    PubMed

    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.

  19. The acute renal actions of angiotensin converting enzyme inhibitors in the sodium-depleted conscious primate are mediated by inhibition of the renin-angiotensin system.

    PubMed

    Humke, U; Levens, N; Wood, J; Hofbauer, K

    1992-01-01

    The purpose of this study was to determine if the changes in renal function acutely produced by an inhibitor of angiotensin converting enzyme (ACE) in the sodium-depleted conscious marmoset can be explained primarily by blockade of the renin-angiotensin system. Intravenous injection of a dose of the ACEI, enalaprilate (2 mg/kg), that produced a maximal lowering of blood pressure (BP), also decreased renal vascular resistance and increased renal blood flow. Glomerular filtration rate was unchanged by enalaprilat, leading to a fall in the filtration fraction. In comparison, a dose of the renin inhibitory monoclonal antibody, R-3-36-16 (0.1 mg/kg), that also produced a maximal fall in BP, produced similar changes in renal hemodynamics to those observed after administration of the ACEI. Combined administration of 2 mg/kg enalaprilat and 0.1 mg/kg R-3-36-16 produced changes in BP and renal hemodynamics similar to those produced by the same doses of either agent administered alone. Enalaprilat (2 mg/kg) significantly increased urine volume (UV) and urinary sodium excretion (UNaV). In contrast, these parameters were not significantly altered by 0.1 mg/kg R-3-36-16. However, when given at a 10-fold higher dose, the monoclonal antibody produced an increase in UNaV and UV identical to that produced by the ACEI alone. Enalaprilat did not increase UV and UNaV excretion to a greater extent than the high dose of the renin inhibitory antibody. These results demonstrate that acute administration of an ACEI affects BP and renal function in the sodium-depleted conscious primate primarily by inhibition of the renin-angiotensin system.

  20. Blockade of the Renin-Angiotensin system improves insulin receptor signaling and insulin-stimulated skeletal muscle glucose transport in burn injury.

    PubMed

    Kasper, Sherry O; Phillips, Erin E; Castle, Scott M; Daley, Brian J; Enderson, Blaine L; Karlstad, Michael D

    2011-01-01

    Burn injury is associated with a decline in glucose utilization and insulin sensitivity due to alterations in postreceptor insulin signaling pathways. We have reported that blockade of the renin-angiotensin system with losartan, an angiotensin II type 1 (AT1) receptor blocker, improves whole body insulin sensitivity and glucose metabolism after burn injury. This study examines whether losartan improves insulin signaling pathways and insulin-stimulated glucose transport in skeletal muscle in burn-injured rats. Rats were injured by a 30% full-skin-thickness scalding burn and treated with losartan or placebo for 3 days after burn. Insulin signaling pathways were investigated in rectus abdominus muscle taken before and 90 s after intraportal insulin injection (10 U·kg). Insulin-stimulated insulin receptor substrate 1-associated phosphatidylinositol 3-kinase and plasma membrane-associated GLUT4 transporter were substantially increased with losartan treatment in burn-injured animals (59% above sham). Serine phosphorylated AKT/PKB was decreased with burn injury, and this decrease was attenuated with losartan treatment. In a separate group of rats, the effect of insulin on 2-deoxyglucose transport was significantly impaired in burned as compared with sham soleus muscles, in vitro; however, treatment of burned rats with losartan completely abolished the reduction of insulin-stimulated 2-deoxyglucose transport. These findings demonstrate a cross talk between the AT1 and insulin receptor that negatively modulates insulin receptor signaling and suggest a potential role of renin-angiotensin system blockade as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle and improving whole-body glucose homeostasis in burn injury.

  1. Diabetic retinopathy and blockade of the renin-angiotensin system: new data from the DIRECT study programme.

    PubMed

    Wright, A D; Dodson, P M

    2010-01-01

    The pathogenesis and medical management of diabetic retinopathy is reviewed. The importance of good control of blood glucose and blood pressure remain key elements in the prevention and treatment of diabetic retinopathy, and a number of specific metabolic pathways have been identified that may be useful additional targets for therapeutic intervention. Trial data, however, aimed specifically to answer the questions of optimum medical management are limited, so the DIRECT study of renin-angiotensin blockade using oral candesartan 32 mg daily is a welcome addition to our knowledge. This arose from the promising improvement of retinopathy outcomes in the EUCLID study of lisinopril in type I diabetes. In DIRECT, 5 years of candesartan treatment in type I diabetes reduced the incidence of retinopathy by two or more steps (EDTRS) in severity by 18% (P=0.0508) and, in a post hoc analysis, reduced the incidence of retinopathy by three-step progression by 35% (P=0.034). In type I diabetes patients there was no effect on progression of established retinopathy. In contrast, in type II diabetes, 5 years of candesartan treatment resulted in 34% regression of retinopathy (P=0.009). Importantly, an overall significant change towards less-severe retinopathy was noted in both type I and II diabetes (P

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

    PubMed Central

    Takahashi, Hakuo

    2012-01-01

    Basic research using animal models points to a causal role of the central nervous system in essential hypertension; however, since clinical research is technically difficult to perform, this connection has not been confirmed in humans. Recently, renal nerve ablation in humans proved to continuously decrease blood pressure in resistant hypertension. Furthermore, when electrical stimulation was continuously applied to the carotid baroreceptor nerve of human adults, their blood pressure lowered. These findings promoted the concept that the central nervous system may actually be involved in the pathogenesis of essential hypertension, which is closely associated with excess sodium intake. We have demonstrated that endogenous digitalis plays a key role in hypertension associated with excess sodium intake via sympathetic activation in rats. Increased sodium concentration inside the brain activates epithelial sodium channels and the renin-angiotensin-aldosterone system in the brain. Aldosterone releases ouabain from neurons in the paraventricular nucleus in the hypothalamus. Angiotensin II and aldosterone of peripheral origin reach the brain to augment sympathetic outflow. Collectively essential hypertension associated with excess sodium intake and obesity, renovascular hypertension, and primary aldosteronism and pseudoaldosteronism all seem to have a common cause originating from the central nervous system. PMID:23316343

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

    PubMed

    Düsing, Rainer

    2016-06-01

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

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

    PubMed

    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.

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

    PubMed Central

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

    2016-01-01

    Background: 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. Methods: 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. Results: 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. Conclusion: 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. PMID:27086671

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

    PubMed

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

    2011-06-01

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

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

    PubMed Central

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

    2016-01-01

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

  8. Effects of alpha1-adrenergic receptor blockade by doxazosin on renin-angiotensin system-regulating aminopeptidase and vasopressin-degrading activities in male and female rat thalamus.

    PubMed

    de la Chica-Rodríguez, S; Cortés-Denia, P; Ramírez-Expósito, M J; Martínez-Martos, J M

    2007-11-01

    The thalamus has connections with central autonomic centers involved in cardiovascular control and is enervated by noradrenergic fibers. The excitability of thalamic neurons is due to a reduction of ionic currents mediated by alpha(1)-adrenoceptors. The brain renin- angiotensin system (RAS) and the peptide hormone arginine-vasopressin (AVP) are also involved in the central control of blood pressure, and fluid and electrolyte homeostasis. It has been extensively reported that aminopeptidase A (APA), aminopeptidase B (APB), aminopeptidase N (APN), and vasopressin-degrading cystyl aminopeptidase activity (AVP-DA) play an important role in the regulation of the activity of angiotensins and AVP. We have analyzed the effect of alpha(1)-adrenoceptor blockade by doxazosin on RAS-regulating aminopeptidase activities and AVP-DA in soluble and membrane-bound fractions of male and female rat thalamus. Our results show that alpha(1)-adrenoceptors blockade by doxazosin does not modify the RAS through its degrading peptidases at thalamic level either in male or female rats. However, alpha(1)-adrenoceptors blockade shows gender differences in AVP-DA, increasing in males but not in females, supporting an increased capacity of males against females to degrade AVP and, therefore, to regulate cardiovascular homeostasis, under this pharmacological manipulation.

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

    PubMed

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

    2015-09-01

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

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

    PubMed

    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.

  11. Recombinant Expression and Characterization of Human and Murine ACE2: Species-Specific Activation of the Alternative Renin-Angiotensin-System

    PubMed Central

    Poglitsch, Marko; Domenig, Oliver; Schwager, Cornelia; Stranner, Stefan; Peball, Bernhard; Janzek, Evelyne; Wagner, Bettina; Jungwirth, Helmut; Loibner, Hans; Schuster, Manfred

    2012-01-01

    Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase of the renin-angiotensin-system (RAS) which is known to cleave several substrates among vasoactive peptides. Its preferred substrate is Angiotensin II, which is tightly involved in the regulation of important physiological functions including fluid homeostasis and blood pressure. Ang 1–7, the main enzymatic product of ACE2, became increasingly important in the literature in recent years, as it was reported to counteract hypertensive and fibrotic actions of Angiotensin II via the MAS receptor. The functional connection of ACE2, Ang 1–7, and the MAS receptor is also referred to as the alternative axis of the RAS. In the present paper, we describe the recombinant expression and purification of human and murine ACE2 (rhACE2 and rmACE2). Furthermore, we determined the conversion rates of rhACE2 and rmACE2 for different natural peptide substrates in plasma samples and discovered species-specific differences in substrate specificities, probably leading to functional differences in the alternative axis of the RAS. In particular, conversion rates of Ang 1–10 to Ang 1–9 were found to be substantially different when applying rhACE2 or rmACE2 in vitro. In contrast to rhACE2, rm ACE2 is substantially less potent in transformation of Ang 1–10 to Ang 1–9. PMID:22518284

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

    PubMed Central

    Wang, Ru; Chen, Junjie; Zhang, Zhenyu; Cen, Ying

    2015-01-01

    Background Histologically, keloids contain excess fibroblasts and an overabundance of dermal collagen. Recently, it was reported that chymase induced a profibrotic response via transforming growth factor-β1 (TGF-β1)/Smad activation in keloid fibroblasts (KFs). However, the role of chymase in the local renin-angiotensin system (RAS) in keloids has not been elucidated. This study aims to determine whether chymase plays an important role in the local RAS in keloids. Methods We compared the expression and activity of chymase in keloids and normal skin tissues using Western blotting and radioimmunoassay, and studied the expression of TGF-β1, interleukin-1β, collagen I, hydroxyproline, and angiotensin II in KFs after chymase and inhibitors’ treatment. Results The results revealed an increased activity of chymase in keloid tissues, and that chymase enhanced the expression of angiotensin II, collagen I, TGF-β1, and interleukin-1β in KFs. Blockade of the chymase pathway involved in the local RAS lowered the expression of these signaling factors. Conclusion This research suggests that inhibition of chymase might be an effective therapeutic approach to improve the clinical treatment of keloids. PMID:26357464

  13. Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS)

    PubMed Central

    De Giusti, V. C.; Caldiz, C. I.; Ennis, I. L.; Pérez, N. G.; Cingolani, H. E.; Aiello, E. A.

    2013-01-01

    Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling 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. PMID:23755021

  14. Role of blood pressure and the renin-angiotensin system in development of diabetic nephropathy (DN) in eNOS-/- db/db mice.

    PubMed

    Zhang, Ming-Zhi; Wang, Suwan; Yang, Shilin; Yang, Haichun; Fan, Xiaofeng; Takahashi, Takamune; Harris, Raymond C

    2012-02-15

    Randomized clinical trials have clearly shown that inhibition of the renin-angiotensin system (RAS) will slow the rate of progression of diabetic nephropathy, but controversy remains about whether the observed beneficial effects result from more than control of blood pressure. Deletion of eNOS in a model of type II diabetes, db/db mice (eNOS(-/-) db/db), induces an accelerated nephropathy and provides an excellent model of human diabetic nephropathy. As is frequently seen in type II diabetes, blood pressure is moderately elevated in eNOS(-/-) db/db mice. To determine the role of elevated blood pressure per se vs. additional deleterious effects of the RAS in mediation of disease progression, 8-wk-old eNOS(-/-) db/db mice were randomly divided into three groups: vehicle, treatment with the angiotensin-converting enzyme inhibitor (ACEI) captopril, or treatment with "triple therapy" (hydralazine, resperine, hydrocholorothiazide), and the animals were euthanized after treatment for 12 wk. Blood pressure was reduced to comparable levels with ACE inhibition or triple therapy. Although both treatment regimens decreased development of diabetic nephropathy, ACE inhibition led to more profound reductions in albuminuria, glomerulosclerosis, markers of tubulointerstitial injury, macrophage infiltration, and markers of inflammation. Therefore, this animal model suggests that while there is an important role for blood pressure control, RAS blockade provides additional benefits in slowing the progression of diabetic nephropathy. PMID:22114203

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

    PubMed Central

    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

  16. The Influence of Long Term Hydrochlorothiazide Administration on the Relationship between Renin-Angiotensin-Aldosterone System Activity and Plasma Glucose in Patients with Hypertension

    PubMed Central

    Xiao, Xu; Du, Hong-jun; Hu, Wei-jian; Shaw, Peter X.

    2013-01-01

    Objective. To observe the relationship between changes in renin-angiotensin-aldosterone system (RAAS) activity and blood plasma glucose after administration of hydrochlorothiazide (HCTZ) for one year in patients with hypertension. Methods. 108 hypertensive patients were given 12.5 mg HCTZ per day for one year. RAAS activity, plasma glucose levels, and other biochemical parameters, as well as plasma oxidized low density lipoprotein (oxLDL) levels, were measured and analyzed at baseline, six weeks, and one year after treatment. Results. After one year of treatment, the reduction in plasma glucose observed between the elevated plasma renin activity (PRA) group (−0.26 ± 0.26 mmol/L) and the nonelevated PRA group (−1.36 ± 0.23 mmol/L) was statistically significant (P < 0.05). The decrease of plasma glucose in the elevated Ang II group (−0.17 ± 0.18 mmol/L) compared to the nonelevated Ang II group (−1.07 ± 0.21 mmol/L) was statistically significant (P < 0.05). The proportion of patients with elevated plasma glucose in the elevated Ang II group (40.5%) was significantly higher than those in the nonelevated Ang II group (16.3%) (P < 0.05). The relative oxLDL level was not affected by the treatment. Conclusions. Changes in RAAS activity were correlated with changes in plasma glucose levels after one year of HCTZ therapy. PMID:24349612

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

    PubMed

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

    2016-07-27

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

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

    NASA Technical Reports Server (NTRS)

    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.

  19. 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.

    PubMed

    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.

  20. Activation of systemic, but not local, renin-angiotensin system is associated with upregulation of TNF-α during prolonged fasting in northern elephant seal pups.

    PubMed

    Suzuki, Miwa; Vázquez-Medina, José Pablo; Viscarra, Jose A; Soñanez-Organis, José G; Crocker, Daniel E; Ortiz, Rudy M

    2013-09-01

    Northern elephant seal pups naturally endure a 2-3 month post-weaning fast that is associated with activation of systemic renin-angiotensin system (RAS), a decrease in plasma adiponectin (Acrp30), and insulin resistance (IR)-like conditions. Angiotensin II (Ang II) and tumor necrosis factor-alpha (TNF-α) are potential causal factors of IR, while Acrp30 may improve insulin signaling. However, the effects of fasting-induced activation of RAS on IR-like conditions in seals are not well described. To assess the effects of prolonged food deprivation on systemic and local RAS, and their potential contribution to TNF-α as they relate to an IR condition, the mRNA expressions of adipose and muscle RAS components and immuno-relevant molecules were measured along with plasma RAS components. Mean plasma renin activity and Ang II concentrations increased by 89 and 1658%, respectively, while plasma angiotensinogen (AGT) decreased by 49% over the fast, indicative of systemic RAS activation. Prolonged fasting was associated with decreases in adipose and muscle AGT mRNA expressions of 69 and 68%, respectively, corresponding with decreases in tissue protein content, suggesting suppression of local AGT production. Muscle TNF-α mRNA and protein increased by 239 and 314%, whereas those of adipose Acrp30 decreased by 32 and 98%, respectively. Collectively, this study suggests that prolonged fasting activates a systemic RAS, which contributes to an increase in muscle TNF-α and suppression of adipose Acrp30. This targeted and tissue-specific regulation of TNF-α and Acrp30 is likely coordinated to synergistically contribute to the development of an IR-like condition, independent of local RAS activity. These data enhance our understanding of the adaptive mechanisms evolved by elephant seals to tolerate potentially detrimental conditions. PMID:23685967

  1. Activation of systemic, but not local, renin-angiotensin system is associated with upregulation of TNF-α during prolonged fasting in northern elephant seal pups.

    PubMed

    Suzuki, Miwa; Vázquez-Medina, José Pablo; Viscarra, Jose A; Soñanez-Organis, José G; Crocker, Daniel E; Ortiz, Rudy M

    2013-09-01

    Northern elephant seal pups naturally endure a 2-3 month post-weaning fast that is associated with activation of systemic renin-angiotensin system (RAS), a decrease in plasma adiponectin (Acrp30), and insulin resistance (IR)-like conditions. Angiotensin II (Ang II) and tumor necrosis factor-alpha (TNF-α) are potential causal factors of IR, while Acrp30 may improve insulin signaling. However, the effects of fasting-induced activation of RAS on IR-like conditions in seals are not well described. To assess the effects of prolonged food deprivation on systemic and local RAS, and their potential contribution to TNF-α as they relate to an IR condition, the mRNA expressions of adipose and muscle RAS components and immuno-relevant molecules were measured along with plasma RAS components. Mean plasma renin activity and Ang II concentrations increased by 89 and 1658%, respectively, while plasma angiotensinogen (AGT) decreased by 49% over the fast, indicative of systemic RAS activation. Prolonged fasting was associated with decreases in adipose and muscle AGT mRNA expressions of 69 and 68%, respectively, corresponding with decreases in tissue protein content, suggesting suppression of local AGT production. Muscle TNF-α mRNA and protein increased by 239 and 314%, whereas those of adipose Acrp30 decreased by 32 and 98%, respectively. Collectively, this study suggests that prolonged fasting activates a systemic RAS, which contributes to an increase in muscle TNF-α and suppression of adipose Acrp30. This targeted and tissue-specific regulation of TNF-α and Acrp30 is likely coordinated to synergistically contribute to the development of an IR-like condition, independent of local RAS activity. These data enhance our understanding of the adaptive mechanisms evolved by elephant seals to tolerate potentially detrimental conditions.

  2. Local stress, not systemic factors, regulate gene expression of the cardiac renin-angiotensin system in vivo: a comprehensive study of all its components in the dog.

    PubMed Central

    Lee, Y A; Liang, C S; Lee, M A; Lindpaintner, K

    1996-01-01

    Cardiac hypertrophy is associated with altered expression of the components of the cardiac renin-angiotensin system (RAS). While in vitro data suggest that local mechanical stimuli serve as important regulatory modulators of cardiac RAS activity, no in vivo studies have so far corroborated these observations. The aims of this study were to (i) examine the respective influence of local, mechanical versus systemic, soluble factors on the modulation of cardiac RAS gene expression in vivo; (ii) measure gene expression of all known components of the RAS simultaneously; and (iii) establish sequence information and an assay system for the RAS of the dog, one of the most important model organisms in cardiovascular research. We therefore examined a canine model of right ventricular hypertrophy and failure (RVHF) in which the right ventricle (RV) is hemodynamically loaded, the left ventricle (LV) is hemodynamically unloaded, while both are exposed to the same circulating milieu of soluble factors. Using specific competitive PCR assays, we found that RVHF was associated with significant increases in RV mRNA levels of angiotensin converting enzyme and angiotensin II type 2 receptor, and with significant decreases of RV expression of chymase and the angiotensin II type 1 receptor, while RV angiotensinogen and renin remained unchanged. All components remained unchanged in the LV. We conclude that (i) dissociated regional regulation of RAS components in RV and LV indicates modulation by local, mechanical, not soluble, systemic stimuli; (ii) components of the cardiac RAS are independently and differentially regulated; and (iii) opposite changes in the expression of angiotensin converting enzyme and chymase, and of angiotensin II type I and angiotensin II type 2 receptors, may indicate different physiological roles of these RAS components in RVHF. Images Fig. 1 PMID:8855304

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

    PubMed

    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 < 0.05). Losartan reduced MAP in both sham and RD rats similarly (numerically and by percentage) (142 ± 10 vs. 161 ± 6 mm Hg; P < 0.05 vs. RD, P < 0.05 vs. baseline). However, female SHR rats remained significantly hypertensive despite both pharmacological intervention and RD. The data suggest that both the renal sympathetic nervous system and the RAS have independent effects to control the blood pressure in old female SHR. Since the denervated rats treated with losartan remained hypertensive, the data also suggest that other mechanisms than the RAS and renal sympathetic nervous system contribute to the hypertension in old female SHR. The data also suggest that multiple mechanisms may mediate the elevated blood pressure in postmenopausal women.

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

    PubMed

    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. PMID:27344167

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

    PubMed

    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.

  6. Comparative effects of pinacidil and prazosin on blood pressure, weight, plasma volume, the renin-angiotensin-aldosterone system, and the renal kallikrein-kinin system in patients with essential hypertension.

    PubMed

    Solomon, R J; Weinberg, M S

    1987-12-01

    Patients with essential hypertension were randomized to treatment with either prazosin or pinacidil, a new direct-acting vasodilator. Factors that might modulate the antihypertensive response and result in pseudotolerance to these drugs were measured before initiation of therapy and following 12 weeks of treatment. Despite significant reductions in blood pressure, pinacidil and prazosin did not produce an increase in plasma volume, did not activate the renin-angiotensin-aldosterone system, and did not interfere with the renal kallikrein-kinin system. The data fail to reveal evidence of physiologic compensatory changes that would lead to the development of pseudotolerance. PMID:3330989

  7. Angiotensin type 1a receptor-deficient mice develop diabetes-induced cardiac dysfunction, which is prevented by renin-angiotensin system inhibitors

    PubMed Central

    2013-01-01

    Background Diabetes-induced organ damage is significantly associated with the activation of the renin-angiotensin system (RAS). Recently, several studies have demonstrated a change in the RAS from an extracellular to an intracellular system, in several cell types, in response to high ambient glucose levels. In cardiac myocytes, intracellular angiotensin (ANG) II synthesis and actions are ACE and AT1 independent, respectively. However, a role of this system in diabetes-induced organ damage is not clear. Methods To determine a role of the intracellular ANG II in diabetic cardiomyopathy, we induced diabetes using streptozotocin in AT1a receptor deficient (AT1a-KO) mice to exclude any effects of extracellular ANG II. Further, diabetic animals were treated with a renin inhibitor aliskiren, an ACE inhibitor benazeprilat, and an AT1 receptor blocker valsartan. Results AT1a-KO mice developed significant diastolic and systolic dysfunction following 10 wks of diabetes, as determined by echocardiography. All three drugs prevented the development of cardiac dysfunction in these animals, without affecting blood pressure or glucose levels. A significant down regulation of components of the kallikrein-kinin system (KKS) was observed in diabetic animals, which was largely prevented by benazeprilat and valsartan, while aliskiren normalized kininogen expression. Conclusions These data indicated that the AT1a receptor, thus extracellular ANG II, are not required for the development of diabetic cardiomyopathy. The KKS might contribute to the beneficial effects of benazeprilat and valsartan in diabetic cardiomyopathy. A role of intracellular ANG II is suggested by the inhibitory effects of aliskiren, which needs confirmation in future studies. PMID:24215514

  8. The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels.

    PubMed

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

    2006-10-01

    Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thus risk for arterial thrombosis. We report here results from a genetic analysis of plasma t-PA and PAI-1 levels in a large population-based sample from the PREVEND study in Groningen, the Netherlands (n = 2,527). We measured polymorphisms from genes of the fibrinolytic system, the renin-angiotensin system (RAS), and the bradykinin system. We found that males had higher levels of natural-log transformed t-PA, and PAI-1 (P < 0.01) compared to females. When stratifying females by menopausal status, PAI-1 levels were only significantly different between pre-menopausal females and males (p < 0.001). Furthermore, we found that age, body mass index, and waist-to-hip ratio were significant predictors of t-PA and PAI-1 in both females and males, and that the regression relationships between these factors and plasma t-PA and PAI-1 were dependent on gender. In addition, we found that the PAI-1 4G/5G polymorphism was a significant predictor of PAI-1 levels in both females and males, that the angiotensin II type I receptor A1166C was a significant predictor of t-PA and PAI-1 levels in females, and that the bradykinin receptor B2 58CT polymorphism was a significant predictor of t-PA levels in females. In conclusion, this large population-based study showed that t-PA and PAI-1 levels are determined by several demographic and genetic factors involved in the fibrinolytic, RAS and bradykinin system. In addition, the results support the idea that the biology of t-PA and PAI-1 is different between females and males.

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

    PubMed Central

    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

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

    PubMed

    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.

  11. Genetic variant of the renin-angiotensin system and prevalence of type 2 diabetes mellitus: a modest but significant effect of aldosterone synthase.

    PubMed

    Ichikawa, Mai; Konoshita, Tadashi; Nakaya, Takahiro; Yamamoto, Katsushi; Yamada, Mika; Sato, Satsuki; Imagawa, Michiko; Makino, Yasukazu; Fujii, Miki; Zenimaru, Yasuo; Arakawa, Kenichiro; Suzuki, Jinya; Ishizuka, Tamotsu; Nakamura, Hiroyuki

    2014-08-01

    Recent genome-wide association studies have identified multiple variants that confer risk of type 2 diabetes mellitus (DM). However, established associations explain only a part of the heritability. Thus, even at the genome-wide association studies era, candidate gene approach should be still useful. Recent interventional studies against the renin-angiotensin system (RAS) showed reduction in new onset of DM, implying the system is involved in the onset. We substantiated the hypothesis that genetic variants of RAS have significant association with prevalence of DM. We enrolled to the study consecutive 782 subjects who had consulted our hospitals for mainly lifestyle related diseases. They consisted of 282 (36.1 %) diabetes cases. Genotypes were assayed with genomic DNA for conventional four genes of the RAS, i.e., angiotensin converting enzyme (ACE) insertion/deletion variant, angiotensinogen (AGT) M235T variant, angiotensin II type I receptor (AT1) A1166C variant, and aldosterone synthase (CYP11B2) C-344T variant. Association between the genetic variants of the RAS and prevalence of type 2 DM was tested. A significant association of DM and CYP11B2 genotype was obtained. There was no significant association between DM and ACE, AGT and AT1 variants. A multivariate logistic regression showed that age, gender, and CYP11B2 genotype were independent factors for association to diabetes, the DM risk of CC/CT to TT being 1.40 (95 % CI 1.04-1.90, p = 0.029). Thus, it is concluded that a genetic variant of the RAS should have a modest but significant impact on the onset of type 2 diabetes mellitus.

  12. 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.

    PubMed

    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.

  13. Which is the optimal antihypertensive combination in different diseases, a renin- angiotensin-aldosterone system inhibitor with a diuretic or with a calcium channel blocker?

    PubMed

    Riva, Nicoletta; Lip, Gregory Y H

    2013-01-01

    Successful treatment of hypertension often requires the association of drugs from different classes. Combination therapy takes advantage of complementary mechanisms of action, in order to reach target blood pressure (BP) earlier and to minimize the side effects of medications. In the last decade, several randomized trials have demonstrated the efficacy of combining a renin-angiotensin-aldosterone system (RAAS) inhibitor with a calcium channel blocker (CCB) or with a diuretic in different populations. The ACCOMPLISH trial was the only large clinical trial that directly compared the two combination strategies. In hypertensive individuals at high cardiovascular risk, benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing the primary composite endpoint of cardiovascular events plus death from cardiovascular causes. Small randomized trials have evaluated the two combination therapies in surrogate endpoints, such as microalbuminuria, with contrasting results. Current European and American guidelines recommend combination therapy as first-line when BP is at least 20/10 mmHg above treatment goals. However, the choice of the best combination therapy is still debated: the National Institute for Health and Clinical Excellence guidelines recommend a RAAS inhibitor plus a CCB, while the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines underline the pivotal role of thiazide diuretics. The combination of a RAAS inhibitor with a CCB demonstrated the best efficacy in reducing cardiovascular endpoint. However, the combination of a RAAS inhibitor with a diuretic has shown beneficial results in particular subgroup of patients, such as patients with heart failure or with African American origin. This review will focus on the rationale and current evidences about combination therapy in the management of arterial hypertension.

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

    PubMed

    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.

  15. Molecular characterization and transcriptional regulation of the renin-angiotensin system genes in Senegalese sole (Solea senegalensis Kaup, 1858): differential gene regulation by salinity.

    PubMed

    Armesto, Paula; Cousin, Xavier; Salas-Leiton, Emilio; Asensio, Esther; Manchado, Manuel; Infante, Carlos

    2015-06-01

    In this work, the complete cDNA sequence encoding angiotensinogen (agt) in the euryhaline flatfish Senegalese sole was obtained. Additionally, putative coding sequences belonging to other renin-angiotensin system (RAS) genes including renin (ren), angiotensin-converting enzyme (ace), angiotensin-converting enzyme 2 (ace2), as well as angiotensin II receptor type I (agtr1) and type II (agtr2), were also identified. In juvenile tissues, agt transcripts were mainly detected in liver, ren in kidney, ace and ace2 in intestine, agtr1 in kidney and brain, and agtr2 in liver and kidney. Expression analysis of the six RAS genes after a salinity shift revealed a clear increase of agt mRNA abundance in liver just after transferring soles to high salinity water (60 ppt) with a peak at 48 h. Moreover, gene expression analysis in gills showed transcriptional regulation of ace and agtr1 at 48 h and agtr2 at 96 h after transferring soles to 60 ppt. Incubation of larvae before mouth opening (until 3 days post hatch; dph) at low salinity (10 ppt) resulted in a coordinated transcriptional up-regulation of RAS genes. Nevertheless, no differences in mRNA abundance between salinities were observed when larvae were cultivated to low salinity after mouth opening. Whole-mount in situ hybridization (WISH) signal for agt and ace in 3 dph larvae incubated at 10 ppt and 35 ppt confirmed that the former gene was mainly expressed in liver whereas the later gene was mainly located in pharynx and posterior gut, without pronounced differences in intensity between salinities. Possible physiological significance of all these results is discussed.

  16. Inhibition of angiotensin-converting enzyme stimulates fracture healing and periosteal callus formation – role of a local renin-angiotensin system

    PubMed Central

    Garcia, P; Schwenzer, S; Slotta, JE; Scheuer, C; Tami, AE; Holstein, JH; Histing, T; Burkhardt, M; Pohlemann, T; Menger, MD

    2010-01-01

    Background and purpose: The renin-angiotensin system (RAS) regulates blood pressure and electrolyte homeostasis. In addition, ‘local’ tissue-specific RAS have been identified, regulating regeneration, cell growth, apoptosis, inflammation and angiogenesis. Although components of the RAS are expressed in osteoblasts and osteoclasts, a local RAS in bone has not yet been described and there is no information on whether the RAS is involved in fracture healing. Therefore, we studied the expression and function of the key RAS component, angiotensin-converting enzyme (ACE), during fracture healing. Experimental approach: In a murine femur fracture model, animals were treated with the ACE inhibitor perindopril or vehicle only. Fracture healing was analysed after 2, 5 and 10 weeks using X-ray, micro-CT, histomorphometry, immunohistochemistry, Western blotting and biomechanical testing. Key results: ACE was expressed in osteoblasts and hypertrophic chondrocytes in the periosteal callus during fracture healing, accompanied by expression of the angiotensin type-1 and type-2 receptors. Perindopril treatment reduced blood pressure and bone mineral density in unfractured femora. However, it improved periosteal callus formation, bone bridging of the fracture gap and torsional stiffness. ACE inhibition did not affect cell proliferation, but reduced apoptotic cell death. After 10 week treatment, a smaller callus diameter and bone volume after perindopril treatment indicated an advanced stage of bone remodelling. Conclusions: Our study provides evidence for a local RAS in bone that influenced the process of fracture healing. We show for the first time that inhibition of ACE is capable of accelerating bone healing and remodelling. PMID:20233225

  17. Similarities and differences of X and Y chromosome homologous genes, SRY and SOX3, in regulating the renin-angiotensin system promoters

    PubMed Central

    Araujo, Fabiano C.; Milsted, Amy; Watanabe, Ingrid K. M.; Del Puerto, Helen L.; Santos, Robson A. S.; Lazar, Jozef; Reis, Fernando M.

    2015-01-01

    The renin-angiotensin system (RAS) is subject to sex-specific modulation by hormones and gene products. However, sex differences in the balance between the vasoconstrictor/proliferative ACE/ANG II/AT1 axis, and the vasodilator/antiproliferative ACE2/ANG-(1–7)/MAS axis are poorly known. Data in the rat have suggested the male-specific Y-chromosome gene Sry to contribute to balance between these two axes, but why the testis-determining gene has these functions remains unknown. A combination of in silico genetic/protein comparisons, functional luciferase assays for promoters of the human RAS, and RNA-Seq profiling in rat were used to address if regulation of Sry on the RAS is conserved in the homologous X-chromosome gene, Sox3. Both SRY and SOX3 upregulated the promoter of Angiotensinogen (AGT) and downregulated the promoters of ACE2, AT2, and MAS, likely through overlapping mechanisms. The regulation by both SRY and SOX3 on the MAS promoter indicates a cis regulation through multiple SOX binding sites. The Renin (REN) promoter is upregulated by SRY and downregulated by SOX3, likely through trans and cis mechanisms, respectively. Sry transcripts are found in all analyzed male rat tissues including the kidney, while Sox3 transcripts are found only in the brain and testis, suggesting that the primary tissue for renin production (kidney) can only be regulated by SRY and not SOX3. These results suggest that SRY regulation of the RAS is partially shared with its X-chromosome homolog SOX3, but SRY gained a sex-specific control in the kidney for the rate-limiting step of the RAS, potentially resulting in male-specific blood pressure regulation. PMID:25759379

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

    PubMed

    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.

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

    PubMed

    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.

  20. Captopril, an angiotensin-converting enzyme inhibitor, possesses chondroprotective efficacy in a rat model of osteoarthritis through suppression local renin-angiotensin system

    PubMed Central

    Tang, Yang; Hu, Xiaopeng; Lu, Xiongwei

    2015-01-01

    Objective: A local tissue-specific renin-angiotensin system (local RAS) has emerged as a regulator of cartilage development and homeostasis. However, no report has described the chondroprotective efficacy of RAS inhibitor. Therefore, we studied the pharmacological function of captopril on hypertrophic differentiation of chondrocytes, cartilaginous degeneration and RAS components expression in a rat model of osteoarthritis (OA). Methods: OA was surgically induced in the right knee of male rats. Animal groups included age matched sham control (sham group), OA placebo (OA group), and OA treated with captopril (CAP group). Eight weeks after the induction of OA, the tibias were isolated and the sagittal sections were stained with Safranin O and Masson-Trichrome. The mRNA and protein expression of RAS components were measured by qRT-PCR and western blotting respectively. Results: The thickness of articular cartilage was reduced in the proximal tibia of the OA group, and decreased thickness of articular cartilage of the OA mice was effectively reversed by captopril treatment. Histological analyses revealed remarkable chondrocytes abnormality in OA rats, which were characterized by a marked expansion of hypertrophic zone and inhibition of proliferative zone of chondrocytes in the epiphyseal growth plate of tibia. However, captopril-treated could reverse chondrocytes abnormality in OA rats. Furthermore, the mRNA and protein expression of RAS components, renin, ACE, Ang II AT1R were upregulated in the proximal tibia of OA rats, however, the AT2R expression was suppressed. Intriguingly, captopril-treated could inhibit the activation of RAS in OA rats. Conclusions: The present study demonstrated that captopril could attenuate OA-induced osteoarticular injury, at least partially, through suppression local RAS. PMID:26550169

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    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.

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

    PubMed Central

    Perez-Gomez, Maria Vanessa; Sanchez-Niño, Maria Dolores; Sanz, Ana Belen; Martín-Cleary, Catalina; Ruiz-Ortega, Marta; Egido, Jesus; Navarro-González, Juan F.; Ortiz, Alberto; Fernandez-Fernandez, Beatriz

    2015-01-01

    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. PMID:26239562

  4. The renin-angiotensin system mediates epidermal growth factor receptor-vitamin D receptor cross-talk in colitis-associated colon cancer

    PubMed Central

    Sadiq, Farhana; Almoghrabi, Anas; Mustafi, Devkumar; Kreisheh, Maggi; Sundaramurthy, Sumana; Liu, Weicheng; Konda, Vani J.; Pekow, Joel; Khare, Sharad; Hart, John; Joseph, Loren; Wyrwicz, Alice; Karczmar, Gregory S.; Li, Yan Chun; Bissonnette, Marc

    2014-01-01

    Purpose We previously showed that epidermal growth factor receptor (EGFR) promotes tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model, whereas vitamin D (VD) suppresses tumorigenesis. EGFR-vitamin D receptor (VDR) interactions, however, are incompletely understood. VD inhibits the renin-angiotensin system (RAS), whereas RAS can activate EGFR. We aimed to elucidate EGFR-VDR cross-talk in colorectal carcinogenesis. Experimental Design To examine VDR-RAS interactions, we treated Vdr+/+ and Vdr/− mice with AOM/DSS. Effects of VDR on RAS and EGFR were examined by Westerns, immunostaining and real time PCR. We also examined the effect of vitamin D3 on colonic RAS in Vdr+/+ mice. EGFR regulation of VDR was examined in hypomorphic EgfrWaved2 (Wa2) and Egfrwildtype mice. Ang II-induced EGFR activation was studied in cell culture. Results Vdr deletion significantly increased tumorigenesis, activated EGFR and βcatenin signaling and increased colonic RAS components: including renin and angiotensin II. Dietary VD3 supplementation suppressed colonic renin. Renin was increased in human colon cancers. In studies in vitro, Ang II activated EGFR and stimulated colon cancer cell proliferation by an EGFR-mediated mechanism. Ang II also activated macrophages and colonic fibroblasts. Compared to tumors from EgfrWaved2 mice, tumors from Egfrwildtype mice showed up-regulated Snail1, a suppressor of VDR, and down-regulated VDR. Conclusions VDR suppresses the colonic RAS cascade, limits EGFR signals and inhibits colitis-associated tumorigenesis, whereas EGFR increases Snail1 and down-regulates VDR in colonic tumors. Taken together, these results uncover a RAS-dependent mechanism mediating EGFR and VDR cross-talk in colon cancer. PMID:25212605

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

    PubMed Central

    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

  6. The effect of perinatal taurine on adult renal function does not appear to be mediated by taurine’s inhibition of the renin-angiotensin system

    PubMed Central

    Roysommuti, Sanya; Kritsongsakchai, Angkana; Wyss, J. Michael

    2016-01-01

    This study tests the hypothesis that perinatal taurine supplementation alters adult renal function by inhibition of the renin-angiotensin system. Female Sprague-Dawley rats were fed normal rat chow and given water alone (Control) or water containing an angiotensin converting enzyme inhibitor (captopril, 400 mg/ml) from conception until delivery (FD) or from delivery until weaning (LD). After weaning, the rats received normal rat chow and tap water. At 7–8 weeks of age, renal function at rest and after acute saline load was studied in conscious, restrained male rats. Body weight, mean arterial pressure, heart rate, effective renal blood flow, and renal vascular resistance were not significantly different among the three groups. Compared to Control, glomerular filtration rate, but not filtration fraction, significantly increased after saline load in both FD and LD groups. Water excretion significantly increased only in FD compared to Control, while fractional water excretion was significantly increased after saline load in both FD and LD groups. Sodium excretion significantly increased after saline load only in FD, while both captopril-treated groups significantly decreased fractional sodium excretion. Potassium excretion significantly increased in both FD and LD groups, while fractional potassium excretion significantly increased at rest in FD and decreased in LD groups after saline load. These effects of perinatal RAS inhibition on adult renal function contrast sharply, and are opposite in many cases to, the effects of perinatal taurine supplementation. Thus, these data suggest that perinatal taurine supplementation does not alter adult renal function through its ability to inhibit the perinatal RAS. PMID:25833535

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

    PubMed Central

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

    2016-01-01

    Objective Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR). Methods The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease. Results Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (tNa), although 24-hour urinary Na excretion (UNaV) remained constant. Daily urinary angiotensinogen excretion (UAGTV, 152±10→82±17 μg/g Cre) reduced (p=0.02). Changes in tubular Na load (r2=0.26) and tNa (r2=0.25) correlated with baseline 24-hour UAGTV. Changes in filtered Na load correlated with changes in nighttime systolic BP (r2=0.17), but not with changes in daytime systolic BP. The change in the tNa to filtered Na load ratio was influenced by the change in daytime UNaV (β=−0.67, F=16.8), rather than the change in nighttime UNaV. Conclusions Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of UAGTV by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events. PMID:27283968

  8. Role of the renin angiotensin system on bone marrow-derived stem cell function and its impact on skeletal muscle angiogenesis.

    PubMed

    de Resende, Micheline M; Stodola, Timothy J; Greene, Andrew S

    2010-08-01

    Autologous bone marrow cell (BMC) transplantation has been shown as a potential approach to treat various ischemic diseases. However, under many conditions BMC dysfunction has been reported, leading to poor cell engraftment and a failure of tissue revascularization. We have previously shown that skeletal muscle angiogenesis induced by electrical stimulation (ES) is impaired in the SS/Mcwi rats and that this effect is related to a dysregulation of the renin angiotensin system (RAS) that is normalized by the replacement of chromosome 13 derived from the Brown Norway rat (SS-13(BN)/Mcwi consomic rats). The present study explored bone marrow-derived endothelial cell (BM-EC) function in the SS/Mcwi rat and its impact on skeletal muscle angiogenesis induced by ES. SS/Mcwi rats were randomized to receive BMC from: SS/Mcwi; SS-13(BN)/Mcwi; SS/Mcwi rats infused with saline or ANG II (3 ng kg(-1) min(-1)). BMC were injected in the stimulated tibialis anterior muscle of SS/Mcwi rats. Vessel density was evaluated in unstimulated and stimulated muscles after 7 days of ES. BMC isolated from SS/Mcwi or SS/Mcwi rats infused with saline failed to restore angiogenesis induced by ES. However, BMC isolated from SS-13(BN)/Mcwi and SS/Mcwi rats infused with ANG II effectively restored the angiogenesis response in the SS/Mcwi recipient. Furthermore, ANG II infusion increased the capacity of BM-EC to induce endothelial cell tube formation in vitro and slightly increased VEGF protein expression. This study suggests that dysregulation of the RAS in the SS/Mcwi rat contributes to impaired BM-EC function and could impact the angiogenic therapeutic potential of BMC.

  9. Novel concept in the mechanism of injury and protection of gastric mucosa: role of renin-angiotensin system and active metabolites of angiotensin.

    PubMed

    Brzozowski, T; Ptak-Belowska, A; Kwiecien, S; Krzysiek-Maczka, G; Strzalka, M; Drozdowicz, D; Pajdo, R; Olszanecki, R; Korbut, R; Konturek, S J; Pawlik, W W

    2012-01-01

    The term cytoprotection pioneered by Robert and colleagues has been introduced to describe the remarkable ability of endogenous and exogenous prostaglandins (PGs) to prevent acute gastric hemorrhagic lesions induced by noxious stimuli such as ethanol, bile acids, hiperosmolar solutions and nonsteroidal anti-inflammatory agents such as aspirin. Since that time many factors were implicated to possess gastroprotective properties such as growth factors including epidermal growth factor (EGF) and transforming factor alpha (TGFα), vasodilatory mediators such as nitric oxide (NO) and calcitonin gene related peptide (CGRP) as well as appetite gut hormones including gastrin and cholecystokinin (CCK), leptin and recently ghrelin. This protective action of gut peptides has been attributed to the release of PG but question remains whether another peptide angiotensin, the classic component of the systemic and local renin-angiotensin system (RAS) could be involved in the mechanism of gastric integrity and gastroprotection. After renin stimulation, the circulating angiotensin I is converted to angiotensin II (ANG II) by the activity of the Angiotensin Converting Enzyme (ACE). The ANG II acting via its binding to two major receptor subtypes the ANG type 1 (AT1) and type 2 (AT2) has been shown be activated during stress and to contribute to the pathogenesis of cold stress- and ischemia-reperfusion-induced gastric lesions. All bioactive angiotensin peptides can be generated not only in systemic circulation, but also locally in several tissues and organs. Recently the new functional components of RAS, such as Ang-(1-7), Ang IV, Ang-(1-12) and novel pathways ACE2 have been described suggesting the gastroprotective role for the novel ANG II metabolite, Ang-(1-7). The fact that Ang-(1-7) is produced in excessive amounts in the gastric mucosa of rodents and that pretreatment by Ang-(1-7) exhibits a potent gastroprotective activity against the gastric lesions induced by cold

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

    PubMed

    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.

  11. An Interaction of Renin-Angiotensin and Kallikrein-Kinin Systems Contributes to Vascular Hypertrophy in Angiotensin II-Induced Hypertension: In Vivo and In Vitro Studies

    PubMed Central

    Ceravolo, Graziela S.; Montezano, Augusto C.; Jordão, Maria T.; Akamine, Eliana H.; Costa, Tiago J.; Takano, Ana P.; Fernandes, Denise C.; Barreto-Chaves, Maria L.; Laurindo, Francisco R.; Tostes, Rita C.; Fortes, Zuleica B.; Chopard, Renato P.; Touyz, Rhian M.; Carvalho, Maria Helena C.

    2014-01-01

    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-Arg9-Leu8-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. Our findings

  12. Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the renin-angiotensin system.

    PubMed

    Kemp, Jacqueline R; Unal, Hamiyet; Desnoyer, Russell; Yue, Hong; Bhatnagar, Anushree; Karnik, Sadashiva S

    2014-10-01

    Improper regulation of signaling in vascular smooth muscle cells (VSMCs) by angiotensin II (AngII) can lead to hypertension, vascular hypertrophy and atherosclerosis. The extent to which the homeostatic levels of the components of signaling networks are regulated through microRNAs (miRNA) modulated by AngII type 1 receptor (AT1R) in VSMCs is not fully understood. Whether AT1R blockers used to treat vascular disorders modulate expression of miRNAs is also not known. To report differential miRNA expression following AT1R activation by AngII, we performed microarray analysis in 23 biological and technical replicates derived from humans, rats and mice. Profiling data revealed a robust regulation of miRNA expression by AngII through AT1R, but not the AngII type 2 receptor (AT2R). The AT1R-specific blockers, losartan and candesartan antagonized >90% of AT1R-regulated miRNAs and AngII-activated AT2R did not modulate their expression. We discovered VSMC-specific modulation of 22 miRNAs by AngII, and validated AT1R-mediated regulation of 17 of those miRNAs by real-time polymerase chain reaction analysis. We selected miR-483-3p as a novel representative candidate for further study because mRNAs of multiple components of the renin-angiotensin system (RAS) were predicted to contain the target sequence for this miRNA. MiR-483-3p inhibited the expression of luciferase reporters bearing 3'-UTRs of four different RAS genes and the inhibition was reversed by antagomir-483-3p. The AT1R-regulated expression levels of angiotensinogen and angiotensin converting enzyme 1 (ACE-1) proteins in VSMCs are modulated specifically by miR-483-3p. Our study demonstrates that the AT1R-regulated miRNA expression fingerprint is conserved in VSMCs of humans and rodents. Furthermore, we identify the AT1R-regulated miR-483-3p as a potential negative regulator of steady-state levels of RAS components in VSMCs. Thus, miRNA-regulation by AngII to affect cellular signaling is a novel aspect of RAS biology

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

    PubMed Central

    2012-01-01

    Background Whether paricalcitol (PCT) reduces proteinuria in the presence of intensified inhibition of Renin-Angiotensin-System (RAS) is poorly studied. We evaluated the antiproteinuric effect of PCT in non-dialysis chronic kidney disease (CKD) patients with proteinuria greater than 0.5 g/24 h persisting despite anti-RAS therapy titrated to minimize proteinuria in the absence of adverse effects. Methods Forty-eight CKD patients were studied in the first six months of add-on oral PCT (1 mcg/day) and three months after drug withdrawal. Results Males were 87.5%, age 63 ± 14 yrs, systolic/diastolic blood pressure (BP) 143 ± 22/78 ± 11 mmHg, eGFR 29.7 ± 14.5 mL/min/1.73 m2, diabetes 40%, and cardiovascular disease 38%. At referral in the center (28 months prior to study baseline), proteinuria was 2.44 (95% CI 1.80-3.04) g/24 h with 6 patients not receiving any anti-RAS and 42 treated with a single agent, at low dosage in most cases. At study baseline, twenty patients were under 2–3 anti-RAS drugs while twenty-eight received 1 agent at full dose and proteinuria resulted to be reduced versus referral to 1.23 g/24 h (95%CI 1.00-1.51). Six months of add-on PCT significantly decreased proteinuria to 0.61 g/24 h (95%CI 0.40-0.93), with levels less than 0.5 g/24 h achieved in 37.5% patients, in the absence of changes of BP and GFR. Proteinuria recovered to basal value after drug withdrawal. The extent of antiproteinuric response to PCT was positively associated with diabetes, eGFR and daily Na excretion (R2 = 0.459, P < 0.0001). PTH decreased from 201 (IQR 92–273) to 83 (IQR 50–189) pg/mL. Conclusions In CKD patients, add-on PCT induces a significant reduction of proteinuria that is evident despite intensified anti-RAS therapy and larger in the presence of diabetes, higher GFR and unrestricted salt intake. PMID:23167771

  14. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials

    PubMed Central

    Fakheri, Robert; Toklu, Bora; Messerli, Franz H

    2016-01-01

    Objective To evaluate the outcomes with use of renin angiotensin system (RAS) blockers compared with other antihypertensive agents in people with diabetes. Design Meta-analysis. Data sources and study selection PubMed, Embase, and the Cochrane central register of controlled trials databases for randomized trials of RAS blockers versus other antihypertensive agents in people with diabetes mellitus. Outcomes were death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, and end stage renal disease. Results The search yielded 19 randomized controlled trials that enrolled 25 414 participants with diabetes for a total of 95 910 patient years of follow-up. When compared with other antihypertensive agents, RAS blockers were associated with a similar risk of death (relative risk 0.99, 95% confidence interval 0.93 to 1.05), cardiovascular death (1.02, 0.83 to 1.24), myocardial infarction (0.87, 0.64 to 1.18), angina pectoris (0.80, 0.58 to 1.11), stroke (1.04, 0.92 to 1.17), heart failure (0.90, 0.76 to 1.07), and revascularization (0.97, 0.77 to 1.22). There was also no difference in the hard renal outcome of end stage renal disease (0.99, 0.78 to 1.28) (power of 94% to show a 23% reduction in end stage renal disease). Conclusions In people with diabetes, RAS blockers are not superior to other antihypertensive drug classes such as thiazides, calcium channel blockers, and β blockers at reducing the risk of hard cardiovascular and renal endpoints. These findings support the recommendations of the guidelines of the European Society of Cardiology/European Society of Hypertension and eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure to also use other antihypertensive agents in people with diabetes but without kidney disease. PMID:26868137

  15. Strong suppression of the renin-angiotensin system has a renal-protective effect in hypertensive patients: high-dose ARB with ACE inhibitor (Hawaii) study.

    PubMed

    Ohishi, Mitsuru; Takeya, Yasushi; Tatara, Yuji; Yamamoto, Koichi; Onishi, Miyuki; Maekawa, Yoshihiro; Kamide, Kei; Rakugi, Hiromi

    2010-11-01

    The principal means for reducing proteinuria in patients with chronic kidney disease are strong blockade of the renin-angiotensin system and strict regulation of blood pressure (BP). This study compared the efficacy of the maximum permissible doses of two common angiotensin receptor blockers (ARBs), namely valsartan (maximum dose=160 mg per day) and olmesartan (maximum dose=40 mg per day). We also investigated whether a high-dose ARB or the combination of an angiotensin-converting enzyme inhibitor with a high-dose ARB would be more renal protective. We recruited 87 poorly controlled hypertensive patients. In the first study, 50 patients without proteinuria were switched from valsartan (160 mg per day) to olmesartan (40 mg per day) for 4 months. In the second study, 37 patients with proteinuria were randomized to either switch from valsartan 160 mg per day to 40 mg per day olmesartan (n=19; Olm-G) or addition of 2.5-10 mg per day imidapril (stepped up by 2.5 mg per month) to valsartan at 160 mg per day (n=18; Imi-G). After 4 months, the BP level decreased (first study) from 157/88 mm Hg to 145/82 mm Hg (P<0.001) and (second study) from 149/86 mm Hg to 135/77 mm Hg and 145/82 mm Hg for Olm-G and Imi-G, respectively. Furthermore, in the second study, urinary protein/creatinine excretion was reduced from 2.0±1.8 g g⁻¹ to 0.8±0.8 g g⁻¹ (P=0.0242) in Olm-G and from 1.4±1.3 g g⁻¹ to 0.9±1.0 g g⁻¹ (P=0.0398) in Imi-G. The significance persisted after adjustment for BP or other risk factors. Our results suggested that the maximum dose of olmesartan was more effective than that of valsartan and comparable with the combination of valsartan and imidapril for reducing BP and proteinuria in poorly controlled hypertensive patients. PMID:20703230

  16. Periarteritis in Lung from a Continuous-Flow Right Ventricular Assist Device: Role of the Local Renin-Angiotensin System

    PubMed Central

    Ootaki, Chiyo; Yamashita, Michifumi; Ootaki, Yoshio; Saeed, Diyar; Horai, Tetsuya; Fumoto, Hideyuki; Massiello, Alex L.; Emancipator, Steven N.; Golding, Leonard A.R.; Fukamachi, Kiyotaka

    2013-01-01

    Background We previously reported renal arterial periarteritis after implantation of a continuous-flow left ventricular assist device in calves. The purpose of the present study was to investigate whether the same periarteritis changes occur in the intrapulmonary arteries after implantation of a continuous-flow right ventricular assist device (CFRVAD) in calves and to determine the mechanism of those histological changes. Methods Ten calves were implanted with a CFRVAD for 29 ± 7 days, and we compared pulmonary artery samples and hemodynamic data pre- and post-CFRVAD implantation prospectively. Results Post implantation, the pulsatility index (pulmonary arterial pulse pressure/pulmonary arterial mean pressure) significantly decreased (pre 0.88 ± 0.40 vs. post 0.51 ± 0.22; p < 0.05), with severe periarteritis of the intrapulmonary arteries in all cases. Periarterial pathology included hyperplasia and inflammatory cell infiltration. The number of inflammatory cells positive for the angiotensin II type 1 receptor was significantly higher after implantation (pre-CFRVAD 7.8 ± 6.5 vs. at autopsy 313.2 ± 145.2; p < 0.01). Serum angiotensin-converting enzyme activity significantly decreased after implantation (pre-CFRVAD 100%, week 1 49.7 ± 17.7%; p = 0.01). Tissue levels of angiotensin-converting enzyme also demonstrated a significant reduction (pre 0.381 ± 0.232 vs. at autopsy 0.123 ± 0.096; p = 0.043). Conclusions Periarteritis occurred in intrapulmonary arteries of calves after CFRVAD implantation. The local renin–angiotensin system (not the angiotensin-converting enzyme pathway) plays an important role in such changes. PMID:23731607

  17. 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.

    PubMed

    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.

  18. 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

    PubMed Central

    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

  19. The effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels are dependent on environmental context.

    PubMed

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

    2007-11-01

    Thrombosis is a key factor in the pathophysiology of cardiovascular disease. Important biochemical constituents of the fibrinolytic system, affecting thrombosis, include tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Both t-PA and PAI-1 are determined by multiple genetic and environmental factors. We aimed to investigate whether the effects of polymorphism in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on t-PA or PAI-1 levels are dependent on environmental factors in a large population-based sample from the PREVEND study in Groningen, The Netherlands (n = 2,527). We found strong evidence (P

  20. 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.

    PubMed

    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.

  1. A low concentration of ouabain (0.18 microg/kg) enhances hypertension in spontaneously hypertensive rats by inhibiting the Na+ pump and activating the renin-angiotensin system.

    PubMed

    Siman, F D M; Stefanon, I; Vassallo, D V; Padilha, A S

    2010-08-01

    We investigated the effects of low ouabain concentrations on systolic (SAP) and diastolic (DAP) arterial pressures and on pressor reactivity in 3-month-old male spontaneously hypertensive rats (SHR). Arterial blood pressure (BP) and pressor reactivity to phenylephrine (PHE) were investigated before and after 0.18 microg/kg ouabain administration (N = 6). The influence of hexamethonium (N = 6), canrenone (N = 6), enalapril (N = 6), and losartan (N = 6) on ouabain actions was evaluated. Ouabain increased BP (SAP: 137 +/- 5.1 to 150 +/- 4.7; DAP: 93.7 +/- 7.7 to 116 +/- 3.5 mmHg; P<0.05) but did not change PHE pressor reactivity. Hexamethonium reduced basal BP in control but not in ouabain-treated rats. However, hexamethonium + ouabain increased DAP sensitivity to PHE. Canrenone did not affect basal BP but blocked ouabain effects on SAP. However, after canrenone + ouabain administration, DAP pressor reactivity to PHE still increased. Enalapril and losartan reduced BP and abolished SAP and DAP responses to ouabain. Enalapril + ouabain reduced DAP reactivity to PHE, while losartan + ouabain reduced SAP and DAP reactivity to PHE. In conclusion, a small dose of ouabain administered to SHR increased BP without altering PHE pressor reactivity. Although the renin-angiotensin system (RAS), Na+ pump and autonomic reflexes are involved in the effects of ouabain on PHE reactivity, central mechanisms might blunt the actions of ouabain on PHE pressor reactivity. The effect of ouabain on SAP seems to depend on the inhibition of both Na+ pump and RAS, whereas the effect on DAP seems to depend only on RAS. PMID:20602018

  2. 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

    PubMed Central

    Wang, La-mei; Tang, Na; Zhong, Hua; Liu, Yong-min; Li, Zhen; Feng, Qian; He, Fang

    2016-01-01

    The proliferation of vascular smooth muscle cells (VSMCs), remodeling of the vasculature, and the renin-angiotensin system (RAS) play important roles in the development of essential hypertension (EH), which is defined as high blood pressure (BP) in which secondary causes, such as renovascular disease, are absent. The calcium-sensing receptor (CaSR) is involved in the regulation of BP. However, the underlying mechanisms by which the CaSR regulates BP are poorly understood. In the present study, the role of the CaSR in EH was investigated using male spontaneously hypertensive rats (SHRs) and rat and human plasma samples. The percentages of medial wall thickness to external diameter (WT%), total vessel wall cross-sectional area to the total area (WA%) of thoracic arteries, as well as the percentage of wall area occupied by collagen to total vessel wall area (CA%) were determined. Tissue protein expression and plasma concentrations of the CaSR, cyclic adenosine monophosphate (cAMP), renin, and angiotensin II (Ang II) were additionally assessed. WT%, WA%, and CA% were found to increase with increasing BP, whereas the plasma concentration of CaSR was found to decrease. With increasing BP, the levels of smooth muscle actin and calponin decreased, whereas those of osteopontin and proliferating cell nuclear antigen increased. The CaSR level negatively correlated with the levels of cAMP and Ang II, but positively correlated with those of renin. Our data suggest that reduced expression of the CaSR is correlated with activation of the RAS, which induces increased vascular remodeling and VSMC proliferation, and thereby associated with EH in the SHR model and in the Han Chinese population. Our findings provide new insights into the pathogenesis of EH. PMID:27391973

  3. 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.

    PubMed

    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.

  4. 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

    PubMed Central

    Lindhardt, Morten; 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 normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy. Methods and analysis Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years. The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples. Ethics and dissemination The study will be conducted under International Conference on Harmonisation – Good clinical practice (ICH-GCP) requirements

  5. [Renin-angiotensin-aldosterone inhibitors for treatment of hypertension with abnormal circadian rhythm of blood pressure].

    PubMed

    Yagi, Shusuke; Sata, Masataka

    2014-08-01

    Circadian rhythm of blood pressure (BP) has recently been focused on because increase in nocturnal BP and morning BP surge have been shown to be risks for cardio-cerebrovascular diseases independent of 24-h BP level. The renin-angiotensin-aldosterone system (RAAS) is involved in BP circadian rhythm, and RAAS inhibitors therefore play an important role in the control of circadian rhythm of BP. Bedtime administration of RAAS inhibitors is more effective than morning administration for reducing nocturnal and morning BP levels in addition to converting the BP profile into a dipper pattern, which is known as chronotherapy. For reducing cardio-cerebro-vascular events, controlling abnormal circadian rhythm of BP in addition to 24-h BP using RAAS inhibitors with optimal time dosing should be considered.

  6. Benefits of Renin-Angiotensin Blockade on Retinopathy in Type 1 Diabetes Vary With Glycemic Control

    PubMed Central

    Harindhanavudhi, Tasma; Mauer, Michael; Klein, Ronald; Zinman, Bernard; Sinaiko, Alan; Caramori, M. Luiza

    2011-01-01

    OBJECTIVE Optimal glycemic control slows diabetic retinopathy (DR) development and progression and is the standard of care for type 1 diabetes. However, these glycemic goals are difficult to achieve and sustain in clinical practice. The Renin Angiotensin System Study (RASS) showed that renin-angiotensin system (RAS) blockade can slow DR progression. In the current study, we evaluate whether glycemic control influenced the benefit of RAS blockade on DR progression in type 1 diabetic patients. RESEARCH DESIGN AND METHODS We used RASS data to analyze the relationships between two-steps or more DR progression and baseline glycemic levels in 223 normotensive, normoalbuminuric type 1 diabetic patients randomized to receive 5 years of enalapril or losartan compared with placebo. RESULTS A total of 147 of 223 patients (65.9%) had DR at baseline (47 of 74 patients [63.5%] in placebo and 100 of 149 patients [67.1%] in the combined treatment groups [P = 0.67]). Patients with two-steps or more DR progression had higher baseline A1C than those without progression (9.4 vs. 8.2%, P < 0.001). There was no beneficial effect of RAS blockade (P = 0.92) in patients with baseline A1C ≤7.5%. In contrast, 30 of 112 (27%) patients on the active treatment arms with A1C >7.5% had two-steps or more DR progression compared with 26 of 56 patients (46%) in the placebo group (P = 0.03). CONCLUSIONS RAS blockade reduces DR progression in normotensive, normoalbuminuric type 1 diabetic patients with A1C >7.5%. Whether this therapy could benefit patients with A1C ≤7.5% will require long-term studies of much larger cohorts. PMID:21715517

  7. Renin-angiotensin blockade resets podocyte epigenome through Kruppel-like Factor 4 and attenuates proteinuria.

    PubMed

    Hayashi, Kaori; Sasamura, Hiroyuki; Nakamura, Mari; Sakamaki, Yusuke; Azegami, Tatsuhiko; Oguchi, Hideyo; Tokuyama, Hirobumi; Wakino, Shu; Hayashi, Koichi; Itoh, Hiroshi

    2015-10-01

    Proteinuria is a central component of chronic kidney disease and an independent risk factor for cardiovascular disease. Kidney podocytes have an essential role as a filtration barrier against proteinuria. Kruppel-like Factor 4 (KLF4) is expressed in podocytes and decreased in glomerular diseases leading to methylation of the nephrin promoter, decreased nephrin expression and proteinuria. Treatment with an angiotensin receptor blocker (ARB) reduced methylation of the nephrin promoter in murine glomeruli of an adriamycin nephropathy model with recovery of KLF4 expression and a decrease in albuminuria. In podocyte-specific KLF4 knockout mice, the effect of ARB on albuminuria and the nephrin promoter methylation was attenuated. In cultured human podocytes, angiotensin II reduced KLF4 expression and caused methylation of the nephrin promoter with decreased nephrin expression. In patients, nephrin promoter methylation was increased in proteinuric kidney diseases with decreased KLF4 and nephrin expression. KLF4 expression in ARB-treated patients was higher in patients with than without ARB treatment. Thus, angiotensin II can modulate epigenetic regulation in podocytes and ARB inhibits these actions in part via KLF4 in proteinuric kidney diseases. This study provides a new concept that renin-angiotensin system blockade can exert therapeutic effects through epigenetic modulation of the kidney gene expression. PMID:26108068

  8. 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

    PubMed Central

    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

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

    PubMed

    Negi, Smita I; Jeong, Euy-Myoung; Shukrullah, Irfan; Veleder, Emir; Jones, Dean P; Fan, Tai-Hwang M; Varadarajan, Sudhahar; Danilov, Sergei M; Fukai, Tohru; Dudley, Samuel C

    2015-01-01

    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 (E h GSH) and cysteine (E h 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 E h 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 E h 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. PMID:26504834

  10. Renin-Angiotensin-Aldosterone Genotype Influences Ventricular Remodeling in Infants with Single Ventricle

    PubMed Central

    Mital, Seema; Chung, Wendy K.; Colan, Steven D.; Sleeper, Lynn A.; Manlhiot, Cedric; Arrington, Cammon B.; Cnota, James F.; Graham, Eric M.; Mitchell, Michael E.; Goldmuntz, Elizabeth; Li, Jennifer S.; Levine, Jami C.; Lee, Teresa M.; Margossian, Renee; Hsu, Daphne T.

    2011-01-01

    Background We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function and response to enalapril in infants with single ventricle. Methods and Results Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with RAAS upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate (eGFR), and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high-risk), and those with <2 homozygous risk genotypes (low-risk) at two time points - before the superior-cavopulmonary-connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: 38 were high-risk, 116 were low-risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and eGFR increased after SCPC in the low-risk (p<0.05) but not the high-risk group. These responses were independent of enalapril treatment. Weight and height z-scores were lower at baseline and height remained lower in the high-risk group at 14 months especially in those receiving enalapril (p<0.05). Conclusions RAAS-upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. RAAS genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume unloading surgery. Follow-up is warranted to assess longterm impact. Clinical Trial Registration Clinical Trials.gov Identifier NCT00113087 PMID:21576655

  11. Effects of Add-on Fluvastatin Therapy in Patients with Chronic Proteinuric Nephropathy on Dual Renin-Angiotensin System Blockade: The ESPLANADE Trial

    PubMed Central

    Ruggenenti, Piero; Perna, Annalisa; Tonelli, Marcello; Loriga, Giacomina; Motterlini, Nicola; Rubis, Nadia; Ledda, Franca; Rota, Stefano; Satta, Andrea; Granata, Antonio; Battaglia, Giovanni; Cambareri, Francesco; David, Salvatore; Gaspari, Flavio; Stucchi, Nadia; Carminati, Sergio; Ene-Iordache, Bogdan; Cravedi, Paolo

    2010-01-01

    Background and objectives: This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade. Design, setting, participants, & measurements: After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat. Results: During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated. Conclusions: In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating. PMID:20671225

  12. Renin-Angiotensin System Suppression Mitigates Experimental Radiation Pneumonitis

    SciTech Connect

    Ghosh, Swarajit N.; Zhang Rong; Fish, Brian L.; Semenenko, Vladimir A.; Li, X. Allen; Moulder, John E.; Jacobs, Elizabeth R.; Medhora, Meetha

    2009-12-01

    Purpose: To find the mitigators of pneumonitis induced by moderate doses of thoracic radiation (10-15 Gy). Methods and Materials: Unanesthetized WAG/RijCmcr female rats received a single dose of X-irradiation (10, 12, or 15 Gy at 1.615 Gy/min) to the thorax. Captopril (an angiotensin-converting enzyme inhibitor) or losartan (an angiotensin receptor blocker) was administered in the drinking water after irradiation. Pulmonary structure and function were assessed after 8 weeks in randomly selected rats by evaluating the breathing rate, ex vivo vascular reactivity, and histopathologic findings. Survival analysis was undertaken on all animals, except those scheduled for death. Results: Survival after a dose of 10 Gy to the thorax was not different from that of unirradiated rats for <=1 year. Survival decreased to <50% by 45 weeks after 12 Gy and by 8-9 weeks after 15 Gy. Captopril (17-56mg/kg/d) improved survival and reduced radiation-induced increases in breathing rate, changes in vascular reactivity, and histopathologic evidence of injury. Radiation-induced increases in the breathing rate were prevented even if captopril was started 1 week after irradiation or if it was discontinued after 5 weeks. Losartan, although effective in reducing mortality, was not as efficacious as captopril in mitigating radiation-induced increases in the breathing rate or altered vasoreactivity. Conclusion: In rats, a moderate thoracic radiation dose induced pneumonitis and morbidity. These injuries were mitigated by captopril even when it was begun 1 week after radiation or if discontinued 5 weeks after exposure. Losartan was less effective in protecting against radiation-induced changes in vascular reactivity or tachypnea.

  13. Pregnancy hypertension, parity, and the renin-angiotensin system.

    PubMed

    Symonds, E M; Broughton Pipkin, F

    1978-11-01

    Factors which influence levels of plasma AII in late pregnancy have been studied in 50 primigravidas and 53 multigravidas. A highly significant relationship has been shown between diastolic blood pressure and plasma AII (r = 0.4190 p less than 0.005) in primigravidas but not in multigravidas (r = 0.205; p less than 0.3). Multiple regression analysis and analysis of covariance have been applied to a series of independent variables with plasma AII as the dependent variable. The single most important variable related to AII levels in primigravidas was diastolic blood pressure whereas in multigravidas it was proteinuria. Rhesus blood group was shown to have a significant effect in both parity groups, Rh-negative primigravid women exhibiting higher values of AII.

  14. Renin-Angiotensin System Suppression Mitigates Experimental Radiation Pneumonitis

    PubMed Central

    Ghosh, Swarajit N.; Zhang, Rong; Fish, Brian L.; Semenenko, Vladimir A.; Li, X. Allen; Moulder, John E.; Jacobs, Elizabeth R.; Medhora, Meetha

    2009-01-01

    Purpose To find mitigators of pneumonitis induced by moderate doses of thoracic radiation (10–15 Gy). Materials and Methods Unanesthetized WAG/RijCmcr female rats received single doses of X-irradiation (10, 12 or 15 Gy at 1.615 Gy/minute) to the thorax. Captopril (an angiotensin converting enzyme inhibitor) or losartan (an angiotensin receptor blocker) was administered in drinking water after irradiation. Pulmonary structure and function were assessed after 8 weeks in randomly selected rats by evaluating breathing rate, ex vivo vascular reactivity and histopathology. Survival analysis was undertaken on all animals except those scheduled for sacrifice. Results Survival following a dose of 10 Gy to the thorax was not different from unirradiated rats up to one year. Survival decreased to less than 50%, by 45 weeks after 12 Gy and by 8–9 weeks after 15 Gy. Captopril (17–56 mg/kg/day) improved survival and reduced radiation-induced increases in breathing rate, changes in vascular reactivity and histopathological evidence of injury. Radiation-induced increases in breathing rate were prevented even if captopril was started 1 week following irradiation or if it was discontinued after 5 weeks. Losartan, though effective in reducing mortality was not as efficacious as captopril in mitigating radiation-induced increases in breathing rate or altered vasoreactivity. Conclusions In rats, a moderate thoracic dose of radiation induced pneumonitis and morbidity. These injuries were mitigated by captopril even when it was commenced 1 week after irradiation or if discontinued after 5 weeks following exposure. Losartan was less effective in protecting against radiation-induced changes in vascular reactivity or tachypnea. PMID:19931735

  15. Association of renin-angiotensin and endothelial nitric oxide synthase gene polymorphisms with blood pressure progression and incident hypertension: prospective cohort study

    PubMed Central

    Conen, David; Glynn, Robert J.; Buring, Julie E.; Ridker, Paul M; Zee, Robert Y.L.

    2009-01-01

    Objective The renin-angiotensin system and endothelial function have both been associated with hypertension. The aim of the present study was to assess the relationship of six previously characterized gene variants in the renin-angiotensin system and the NOS3 gene with blood pressure progression and incident hypertension. Methods We analyzed data from 18436 Caucasian women who participated in a prospective cohort study and were free of hypertension at baseline. Six previously characterized single nucleotide polymorphisms (NOS3 rs1800779, NOS3 rs3918226, NOS3 rs1799983, ACE rs1799752, AGT rs699, and AGTR1 rs5186) were genotyped. Blood pressure progression at 48 months and incident hypertension during the entire follow-up according to the different genotypes and inferred haplotypes were assessed by logistic regression and Cox proportional-hazards models, respectively. Results At 48 months, 47.4% of the women had blood pressure progression. The odds ratios (95% confidence intervals (CI)) for blood pressure progression associated with NOS3 rs1800779, NOS3 rs3918226, NOS3 rs1799983, ACE rs1799752, AGT rs699, and AGTR1 rs5186 were 1.00 (0.96–1.05), 1.00 (0.92–1.09), 0.99 (0.94–1.04), 0.96 (0.92–1.01), 1.04 (0.99–1.08), and 1.03 (0.98–1.08). During 9.8 years of follow-up, 29.6% of women developed incident hypertension. The hazard ratios (95% CI) for the six polymorphisms were 1.01 (0.97–1.06), 1.06 (0.99–1.14), 1.05 (1.01–1.09), 0.99 (0.95–1.02), 1.01 (0.97–1.05) and 0.99 (0.95–1.04). NOS3-haplotypes were not significantly associated with blood pressure progression (p=0.91) or incident hypertension (p=0.10). Conclusion Blood pressure progression and incident hypertension are not consistently associated with six well-characterized genetic polymorphisms of the renin-angiotensin system and the NOS3 gene in a large cohort of Caucasian women. PMID:18698212

  16. Involvement of insulin-regulated aminopeptidase in the effects of the renin-angiotensin fragment angiotensin IV: a review.

    PubMed

    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.

  17. Gastrointestinal potassium binding-more than just lowering serum [K(+)]: patiromer, potassium balance, and the renin angiotensin aldosterone axis.

    PubMed

    Emmett, Michael; Mehta, Ankit

    2016-09-01

    Hyperkalemia limits the use of renin-angiotensin-aldosterone axis (RAAS) blockers in patients with renal insufficiency. This can be managed by efforts to increase kaliuresis and by gastrointestinal potassium binding with sodium polystyrene sulfonate, a relatively ineffective agent. Now with the availability of patiromer, RAAS blockers can be used more liberally. In addition, potassium reduction decreases aldosterone, which may be beneficial. Adverse nonepithelial aldosterone effects such as endothelial dysfunction and cardiac fibrosis may be ameliorated. PMID:27521112

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

    PubMed

    Sulzberger, L; Baillie, R; Itinteang, T; de Jong, S; Marsh, R; Leadbitter, P; Tan, S T

    2016-03-01

    The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by β-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low-dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH.

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

    PubMed

    Sulzberger, L; Baillie, R; Itinteang, T; de Jong, S; Marsh, R; Leadbitter, P; Tan, S T

    2016-03-01

    The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by β-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low-dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH. PMID:26612192

  20. Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition.

    PubMed

    Oikawa, T; Freeman, M; Lo, W; Vaughan, D E; Fogo, A

    1997-01-01

    We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P < 1.001 vs. normal control). In situ hybridization revealed significant association of PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombosis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4+ scale, 0.49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0.02 in captopril, enalapril and AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P < 0.05, < 0.01, < 0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.

  1. SY 12-1 RENIN ANGIOTENSIN PATHWAY BEYOND ACE AND ANGIOTENSIN II RECEPTORS: HOW IT RELATES TO THE PATHOPHYSIOLOGY OF HYPERTENSION.

    PubMed

    Burrell, Louise

    2016-09-01

    The renin-angiotensin system (RAS) plays a major role in the pathogenesis of hypertension, a major risk factor for stroke, coronary events, heart failure and kidney disease. Within the RAS, angiotensin converting enzyme (ACE) converts angiotensin (Ang) I into the vasoconstrictor Ang II, which mediates its effects via the angiotensin type 1 receptor (AT1R). An "alternate" arm of the RAS is now known to exist in which the monocarboxypeptidase ACE2 counterbalances the effects of the classic RAS through degradation of the vasoconstrictor peptide, Ang II, and generation of the vasodilatory peptide, Ang 1-7. ACE2 is highly expressed in tissues of cardiovascular relevance including the heart, blood vessels and kidney. The catalytically active ectodomain of ACE2 undergoes shedding resulting in ACE2 in the circulation. The finding that the ACE2 gene maps to a quantitative trait locus on the X chromosome in three strains of genetically hypertensive rats suggests that the ACE2 gene may be a candidate gene for hypertension. It is hypothesised that disruption of tissue ACE/ACE2 balance results in changes in blood pressure, with increased ACE2 expression protecting against increased blood pressure, and ACE2 deficiency contributing to hypertension. Studies in experimental models of hypertension have measured ACE2 gene, protein and/or activity, in either the heart or kidney and/or plasma, usually at one time point, and most commonly in animals with established hypertension. As experimental studies report that deletion or inhibition of ACE2 leads to hypertension, whilst enhancing ACE2 protects against the development of hypertension, increasing or activating ACE2 may be a therapeutic option for the management of high blood pressure in man. There have been relatively few studies of ACE2, either at the gene or the circulating level in patients with hypertension. The available data indicates that plasma ACE2 activity is low in healthy subjects, but elevated in patients with

  2. [Renin-angiotensin system under extracorporeal circulation during heart valve surgery].

    PubMed

    Heck, I; Hack, G; Wickenhöfer, R

    1983-08-01

    Angiotensin I (A I), angiotensin II (A II) and the activity of angiotensin-converting enzyme (ACE) were measured in 15 patients undergoing cardiopulmonary bypass for mitral or aortic valve replacement. During cardiopulmonary bypass A I, A II, A I/II ratio and arteriovenous A II--difference decreased markedly, whereas the activity of ACE fell only during a small 15 min period after start of extracorporeal circulation. Possible reasons for these effects are discussed.

  3. Hypovolemia in syncope and orthostatic intolerance role of the renin-angiotensin system

    NASA Technical Reports Server (NTRS)

    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.

  4. Role of renin angiotensin system inhibitors in cardiovascular and renal protection: a lesson from clinical trials.

    PubMed

    Stojiljkovic, Ljuba; Behnia, Rahim

    2007-01-01

    Beneficial effects of angiotensin converting enzyme inhibitors (ACEI) and angiotensin type 1 receptor (AT1) blockers in patients with cardiovascular and renal diseases have been clearly demonstrated in numerous large outcomes studies. In patients with heart failure (HF), ACEI have been shown to reduce overall mortality, mortality from cardiovascular causes, to increase life expectancy, as well as to preserve the renal function (CONSENSUS, SAVE, TRACE, AIRE, AIREX, CATS trials). In addition, in the PROGRESS study ACEI substantially decreased the risk of stroke and transient ischemic attacks in patients with cerebrovascular disorders. The HOPE and EUROPA studies confirmed that long term therapy with ACEI provides significant survival benefit in patients with broad range of atherosclerotic cardiovascular diseases. After these large and well designed clinical studies, ACEI have become standard therapy for routine secondary prevention in all patients with cardiovascular diseases, unless contraindicated. AT1 receptor blockers have been recently added to the cardiovascular therapeutic armamentarium. They are believed to provide additional protection by inhibition of locally synthesized angiotensin II on the level of AT1 receptor. The ELITE II, ValHeFT and CHARM studies have shown that AT1 receptor blockers are equally effective as ACEI in reduction of mortality and morbidity in patients with HF. Importantly, they may be used together with ACEI, or as alternative treatment in ACEI intolerant patients. Renal protection is another important effect of both ACEI and AT1 blockers that has been confirmed in several large clinical trials. The North American Microalbuminemia Study group and EUCLID group demonstrated significant reduction in progression of diabetic nephropathy in patients with insulin dependent diabetes mellitus (IDDM) treated with ACEI. AT1 receptor blockers are mainly studied in the non-insulin dependent diabetes mellitus (NIDDM) nephropathy. Four recent clinical trials (IRMA-2, DETAIL, RENAAL and IDNT) examined the effect of AT1 receptor blockers in patients with NIDDM nephropathy. These studies confirmed the beneficial effect of AT1 receptor blockers in patients with NIDDM nephropathy that was extended beyond the blood pressure reduction. Ongoing studies (ONTARGET, TRANSCEND and PROTECTION) should provide us with additional insights about cardiovascular, renal and other end-organ protective effects of these therapeutics.

  5. The Renin-Angiotensin-Aldosterone System in Vascular Inflammation and Remodeling

    PubMed Central

    Pacurari, Maricica; Kafoury, Ramzi; Tchounwou, Paul B.; Ndebele, Kenneth

    2014-01-01

    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. PMID:24804145

  6. Carotid Artery Intima-Media Thickness and the Renin-Angiotensin System

    PubMed Central

    Johnson, Christopher T.; Brewster, Luke P.

    2014-01-01

    Carotid artery intima-media thickness (IMT) is a biomarker for cardiovascular disease that also predicts the risk of cardiovascular mortality. Angiotensin-converting enzyme (ACE) inhibition is a unique therapeutic modality because it both treats hypertension and improves arterial health and cardiovascular disease outcomes. Controversy exists regarding the role of ACE inhibitors and angiotensin receptor blockers (ARBs) in IMT regression. Our article provides an update on how ACE inhibitors and ARBs could play a role in decreasing IMT. PMID:23680737

  7. Obesity-induced hypertension develops in young rats independently of the renin-angiotensin-aldosterone system.

    PubMed

    Smith, Anita D; Brands, Michael W; Wang, Mong-Heng; Dorrance, Anne M

    2006-03-01

    A correlation exists between obesity and hypertension. In the currently available models of diet-induced obesity, the treatment of rats with a high fat (HF) diet does not begin until adulthood. Our aim was to develop and characterize a model of pre-pubescent obesity-induced hypertension. Male Sprague-Dawley rats were fed a HF diet (35% fat) for 10 weeks, beginning at age 3 weeks. Blood pressure was measured by tail-cuff, and a terminal blood sample was obtained to measure fasting blood glucose, insulin, plasma renin, aldosterone, thiobarbitutic acid reactive substances (TBARS), and free 8-isoprostanes levels. The vascular reactivity in the aorta was assessed using a myograph. Blood pressure was increased in rats fed the HF diet (HF, 161 +/- 2 mm Hg vs. control, 137 +/- 2 mm Hg, P < 0.05). Blood glucose (HF, 155 +/- 4 mg/dL vs. control, 123 +/- 5 mg/dL, P < 0.05), insulin (HF, 232 +/- 63 pM vs. control, 60 +/- 11 pM, P < 0.05), TBARS (expressed as nM of malondialdehyde [MDA]/ml [HF, 1.8 +/- 0.37 nM MDA/ml vs. control 1.05 +/- 0.09 nM MDA/ml, P < 0.05]), and free 8-isoprostanes (HF, 229 +/- 68 pg/ml vs. control, 112 +/- 9 pg/ml, P < 0.05) levels were elevated in the HF diet group. Interestingly, plasma renin and aldosterone levels were not different between the groups. The maximum vasoconstriction to phenylephrine (10(-4) M) was increased in the HF diet group (HF, 26.1 +/- 1.5 mN vs. control 22.3 +/- 1.2 mN, P < 0.05). In conclusion, pre-pubescent rats become hypertensive and have increased oxidative stress and enhanced vasoconstriction when fed a HF diet. Surprisingly, this occurs without the increase in renin or aldosterone levels seen in the adult models of diet-induced obesity.

  8. Midkine, a newly discovered regulator of the renin-angiotensin pathway in mouse aorta: significance of the pleiotrophin/midkine developmental gene family in angiotensin II signaling.

    PubMed

    Ezquerra, Laura; Herradon, Gonzalo; Nguyen, Trang; Silos-Santiago, Inmaculada; Deuel, Thomas F

    2005-07-29

    We previously demonstrated that pleiotrophin (PTN the protein, Ptn the gene) highly regulates the levels of expression of the genes encoding the proteins of the renin-angiotensin pathway in mouse aorta. We now demonstrate that the levels of expression of these same genes are significantly regulated in mouse aorta by the PTN family member midkine (MK the protein, Mk the gene); a 3-fold increase in expression of renin, an 82-fold increase in angiotensinogen, a 6-fold decrease in the angiotensin converting enzyme, and a 6.5-fold increase in the angiotensin II type 1 and a 9-fold increase in the angiotensin II type 2 receptor mRNAs were found in Mk-/- mouse aorta in comparison with the wild type (WT, +/+). The results in Mk-/- mice are remarkably similar to those previously reported in Ptn-/- mouse aorta, with the single exception of that the levels of the angiotensinogen gene expression in Ptn-/- mice are equal to those in WT+/+ mouse aorta, and thus, in contrast to Mk gene expression unaffected by levels of Ptn gene expression. The data indicate that MK and PTN share striking but not complete functional redundancy. These data support potentially high levels importance of MK and the MK/PTN developmental gene family in downstream signals initiated by angiotensin II either in development or in the many pathological conditions in which MK expression levels are increased, such as atherosclerosis and many human neoplasms that acquire constitutive endogenous Mk gene expression by mutation during tumor progression and potentially provide a target through the renin-angiotensin pathway to treat advanced malignancies.

  9. New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) II: Albumin Suppresses Angiotensin Converting Enzyme (ACE) Activity in Human

    PubMed Central

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

    2014-01-01

    About 8% of the adult population is taking angiotensin-converting enzyme (ACE) inhibitors to treat cardiovascular disease including hypertension, myocardial infarction and heart failure. These drugs decrease mortality by up to one-fifth in these patients. We and others have reported previously that endogenous inhibitory substances suppress serum ACE activity, in vivo, similarly to the ACE inhibitor drugs. Here we have made an effort to identify this endogenous ACE inhibitor substance. ACE was crosslinked with interacting proteins in human sera. The crosslinked products were immunoprecipitated and subjected to Western blot. One of the crosslinked products was recognized by both anti-ACE and anti-HSA (human serum albumin) antibodies. Direct ACE-HSA interaction was confirmed by binding assays using purified ACE and HSA. HSA inhibited human purified (circulating) and human recombinant ACE with potencies (IC50) of 5.7±0.7 and 9.5±1.1 mg/mL, respectively. Effects of HSA on the tissue bound native ACE were tested on human saphenous vein samples. Angiotensin I evoked vasoconstriction was inhibited by HSA in this vascular tissue (maximal force with HSA: 6.14±1.34 mN, without HSA: 13.54±2.63 mN), while HSA was without effects on angiotensin II mediated constrictions (maximal force with HSA: 18.73±2.17 mN, without HSA: 19.22±3.50 mN). The main finding of this study is that HSA was identified as a potent physiological inhibitor of the ACE. The enzymatic activity of ACE appears to be almost completely suppressed by HSA when it is present in its physiological concentration. These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo. PMID:24691203

  10. Effect of Renin Angiotensin System Blockade on Pentraxin 3 Levels in Type-2 Diabetic Patients With Proteinuria

    PubMed Central

    Yilmaz, Mahmut Ilker; Axelsson, Jonas; Sonmez, Alper; Carrero, Juan Jesus; Saglam, Mutlu; Eyileten, Tayfun; Caglar, Kayser; Kirkpantur, Alper; Celik, Turgay; Oguz, Yusuf; Vural, Abdulgaffar; Yenicesu, Mujdat; Lindholm, Bengt; Stenvinkel, Peter

    2009-01-01

    Background and objectives: Long pentraxin 3 (PTX3) is a multimeric inflammatory mediator. Increased serum PTX3 levels have been reported among end-stage renal disease patients. Moreover, PTX3 has been suggested to represent a novel mortality risk factor, and elevated PTX3 levels have been shown to accompany increased albuminuria among patients with chronic kidney disease (CKD). Design, setting, participants, & measurements: We analyzed data of 49 persons with stage 1 diabetic CKD and 32 healthy subjects in a prospective controlled trial. Endothelial dysfunction was determined by flow-mediated dilation (FMD). Serum PTX3, high-sensitivity C-reactive protein (hs-CRP) levels, and FMD were studied in baseline and after 12 wk of ramipril therapy. Stepwise multivariate regression analysis evaluated the association of FMD with clinical and serologic parameters. Results: Serum PTX3, hsCRP, and albumin levels and proteinuria were significantly decreased, and FMD levels were significantly increased, after ramipril treatment. FMD was negatively correlated with serum PTX3, 24-h proteinuria, and hsCRP levels and positively correlated to serum albumin both at baseline and after the 12-wk treatment period. Multivariate regression analysis revealed that PTX3 levels were independently related to FMD both before and after ramipril treatment. Conclusions: Our study shows that serum PTX3 levels are associated with endothelial dysfunction in patients with stage 1 diabetic CKD, independent of CRP. In addition, short-term ACE-inhibitor treatment significantly improves FMD and normalizes PTX3, hsCRP, and urinary protein excretion. (NCT: The study was registered in clinicaltrials.gov as NCT00674596.) PMID:19211665

  11. Renin-Angiotensin System Genes and Exercise Training-Induced Changes in Sodium Excretion in African American Hypertensives

    PubMed Central

    Jones, Jennifer M.; Park, Jung-Jun; Johnson, Jennifer; Vizcaino, Dave; Hand, Brian; Ferrell, Robert; Weir, Matthew; Dowling, Thomas; Obisesan, Thomas; Brown, Michael

    2008-01-01

    Objective To determine whether angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) genotypes could predict changes in urinary sodium excretion in response to short-term aerobic exercise training (AEX). Design Longitudinal intervention. Setting The study was conducted at the University of Maryland at College Park and at Baltimore, and the University of Pittsburgh General Clinical Research Center. Participants 31 (age 53 ± 2 years) sedentary, hypertensive (146 ± 2/88 ± 2 mm Hg) African Americans. Intervention Aerobic exercise training (AEX) consisted of seven or eight consecutive days, 50 minutes per day, at 65% of heart rate reserve. Participants underwent a 24-hour period of ambulatory blood pressure (BP) monitoring and urine collection at baseline and 14–18 hours after the last exercise session. Main Outcome Measures Angiotensiongen (AGT) M235T and ACE I/D genotype and sodium excretion and ambulatory BP. Results Average sodium excretion for the entire group independent of genotype increased after AEX (108 ± 9 vs 143 ± 12 mEq/day, P=.003). Sodium excretion significantly increased after exercise training in the ACE II (114 ± 22 vs 169 ± 39 mEq/day, P=.04), but not in the ID (100 ± 8 vs 133 ± 17 mEq/day, P=.12) or DD (113 ± 18 vs 138 ± 11 mEq/day, P=.13) genotype groups. In the II genotype group, the increase in sodium excretion was significantly and inversely correlated with decreases in 24-hour diastolic (r=−.88, P=.02) and mean (r=−.95, P=.004) BP. The AGT TT and MT+MM genotype groups similarly increased their sodium excretion by 34 ± 16 (P=.05) and 37 ± 17 (P=.05) mEq/day respectively. Conclusions These results suggest that African American hypertensives with the ACE II genotype may be more susceptible to sodium balance and BP changes with exercise training compared with those with the ID and DD genotypes. PMID:16937603

  12. Responses of sympathoadrenal and renin angiotensin systems to stress stimuli in humans during real and simulated microgravity.

    PubMed

    Kvetnansky, R; Koska, J; Ksinantova, L; Noskov, V B; Blazicek, P; Marko, M; Macho, L; Grigoriev, A I; Vigas, M

    2002-07-01

    Changes of plasma hormone levels were investigated in human subjects after exposure to physical exercise (WL) and insulin induced hypoglycemia (ITT) during space flight or after head down bed rest (HDBR). Exaggerated responses of plasma epinephrine (EPI), norepinephrine (NE) and aldosterone (ALD) were observed after WL during space flight as compared to preflight response. Hypoglycemia during space flight induced attenuated responses of EPI, NE and augmented response of ALD. Exposure to WL during HDBR was followed by significantly exaggerated responses of plasma EPI, NE, ALD, PRA and cortisol. In HDBR the responses of plasma EPI, NE and cortisol were reduced and PRA response was exaggerated during ITT. These data indicate that hormonal responses to ITT and WL are similar at real and simulated microgravity. PMID:14977002

  13. Renin-angiotensin-aldosterone system and electrolyte metabolism in rat blood after flight aboard Cosmos-1129 biosatellite

    SciTech Connect

    Kvetnansky, R.; Tigranyan, R.A.; Jindra, A.; Viting, T.A.

    1982-08-01

    Blood plasma aldosterone concentration and renin activity were studied in rats flow in space on the Cosmos 1129 satellite using radioimmunoassay techniques. Immediately after the flight, the animals presented significant decreases in plasma renin activity, as compared to rats in the vivarium control and animals in the synchronous experiment. R. J.

  14. Dual cure photocatalyst systems

    SciTech Connect

    DeVoe, R.J.; Brown-Wensley, K.A.; Holmes, G.L.; Mathis, M.D.; McCormick, F.B.; Palazzotto, M.C.; Spurgeon, K.M. . Corporate Research Labs.)

    1990-01-01

    A family of dual cure photocatalyst systems is being developed to be used in the solventless processing of organic coatings. The photocatalyst systems consist of organometallic compounds often in combination with other agents. Upon photolysis, the photocatalyst system generates a Lewis acid and a free radical. The Lewis acid can initiate the polymerization of epoxies or the addition of isocyanates and polyols to form polyurethanes while the free radical can initiate the polymerization of acrylates. The performance of the various photocatalyst systems will be compared on the basis of the physical properties of the cured compositions they produce. 17 figs.

  15. Dual Tank Fuel System

    DOEpatents

    Wagner, Richard William; Burkhard, James Frank; Dauer, Kenneth John

    1999-11-16

    A dual tank fuel system has primary and secondary fuel tanks, with the primary tank including a filler pipe to receive fuel and a discharge line to deliver fuel to an engine, and with a balance pipe interconnecting the primary tank and the secondary tank. The balance pipe opens close to the bottom of each tank to direct fuel from the primary tank to the secondary tank as the primary tank is filled, and to direct fuel from the secondary tank to the primary tank as fuel is discharged from the primary tank through the discharge line. A vent line has branches connected to each tank to direct fuel vapor from the tanks as the tanks are filled, and to admit air to the tanks as fuel is delivered to the engine.

  16. Modulatory effect of the renin-angiotensin system on the plasma levels of calcitonin gene-related peptide in normal man.

    PubMed

    Portaluppi, F; Vergnani, L; Margutti, A; Ambrosio, M R; Bondanelli, M; Trasforini, G; Rossi, R; Degli Uberti, E C

    1993-09-01

    Calcitonin gene-related peptide (CGRP) has positive chronotropic and inotropic effects in animals and humans, and produces the most potent vasodilation known for an endogenous peptide. Yet, a physiological role for CGRP in the regulation of vascular tone and blood pressure has not been demonstrated. We studied the effects of 1) assumption of the upright position and 2) iv infusion of angiotensin-II (sequential doses of 8, 16, and 32 ng/kg.min, each dose for 20 min) in eight normal subjects (four men). Serial venous blood samples were taken to determine the plasma CGRP, epinephrine, norepinephrine, and aldosterone levels and PRA. Blood pressure and heart rate were continuously monitored at the finger with a Finapres 2300 instrument. After assumption of the upright posture, a quick rise in plasma CGRP levels was observed together with the expected increases in plasma norepinephrine and aldosterone and PRA. A transient increment was also observed for diastolic blood pressure and heart rate. Angiotensin-II infusion caused dose-dependent increases in plasma CGRP and aldosterone concentrations, already significant at the lowest infusion rate and parallel with the blood pressure rise. Plasma catecholamines significantly increased only at higher infusion rates. Our data demonstrate that modifications of plasma CGRP concentrations are part of the normal response to postural and vasomotor changes. These findings suggest a physiological role for CGRP in regulation of the peripheral vascular tone and possibly blood pressure in man.

  17. Increased expression of gp91phox homologues of NAD(P)H oxidase in the aortic media during chronic hypertension: involvement of the renin-angiotensin system.

    PubMed

    Akasaki, Takashi; Ohya, Yusuke; Kuroda, Junya; Eto, Kimika; Abe, Isao; Sumimoto, Hideki; Iida, Mitsuo

    2006-10-01

    Although vascular cells express multiple members of the Nox family of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, including gp91phox, Nox1, and Nox4, the reasons for the different expressions and specific roles of these members in vascular injury in chronic hypertension have remained unclear. Thus, we quantified the mRNA expressions of these NAD(P)H oxidase components by real-time polymerase chain reaction and evaluated superoxide production and morphological changes in the aortas of 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar Kyoto rats (WKY). The aortic media of SHRSP had an approximately 2.5-fold greater level of Nox4 mRNA and an approximately 10-fold greater level of Nox1 mRNA than WKY. The mRNA expressions of gp91phox and p22phox in SHRSP and WKY were comparable. SHRSP were treated from 24 weeks of age for 8 weeks with either high or low doses of candesartan (4 mg/kg/day or 0.2 mg/kg/day), or a combination of hydralazine (30 mg/kg/day) and hydrochlorothiazide (4.5 mg/kg/day). The high-dose candesartan or the hydralazine plus hydrochlorothiazide decreased the blood pressure of SHRSP to that of WKY, whereas the low-dose candesartan exerted no significant antihypertensive action. Media thickening and fibrosis, as well as the increased production of superoxide in SHRSP, were nearly normalized with high-dose candesartan and partially corrected with low-dose candesartan or hydralazine plus hydrochlorothiazide. These changes by antihypertensive treatment paralleled the decrease in mRNA expression of Nox4 and Nox1. These results suggest that blood pressure and angiotensin II type 1 receptor activation are involved in the up-regulation of Nox1 and Nox4 expression, which could contribute to vascular injury during chronic hypertension. PMID:17283869

  18. Prevention of atrial fibrillation with renin-angiotensin system inhibitors on essential hypertensive patients: a meta-analysis of randomized controlled trials

    PubMed Central

    Zhao, Di; Wang, Ze-Mu; Wang, Lian-Sheng

    2015-01-01

    Abstract We aimed to investigate the effectiveness and safety of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on preventing atrial fibrillation in essential hypertensive patients. Systematic literature retrieval was carried out to obtain randomized controlled trials on the effects of ACEI/ARBs on essential hypertensive patients before December, 2013. Data extraction and quality evaluation were performed. Meta-analysis was performed by Review Manager 5.2.3. Ten high quality studies (11 articles) with a total of 42,892 patients (20,491 patients in the ACEI/ARBs group and 22,401 patients in the β-blocker or the calcium antagonist group) met the inclusion criteria and were included in the meta-analysis. The results showed that ACEI/ARBs reduced the incidence of atrial fibrillation (AF) recurrence compared to calcium antagonists (RR = 0.48; 95%CI, 0.40-0.58; P<0.00001) or β-blockers (RR = 0.39; 95%CI, 0.20-0.74; P = 0.005) in long-term follow-up, respectively. Furthermore, ACEI/ARBs reduced the incidence of congestive heart failure (RR = 0.86; 95%CI, 0.77-0.96; P = 0.007). However, no significant effects were observed on the incidence of new AF, cardiac death, myocardial infarction, and stroke. Our results suggest that ACEI/ARBs may reduce the incidence of AF recurrence and congestive heart failure, with fewer serious adverse effects. PMID:26668582

  19. 25 (OH) Vitamin D Levels and Renal Disease Progression in Patients with Type 2 Diabetic Nephropathy and Blockade of the Renin-Angiotensin System

    PubMed Central

    Luño, José; Barrio, Vicente; de Vinuesa, Soledad García; Praga, Manuel; Goicoechea, Marian; Lahera, Vicente; Casas, Luisa; Oliva, Jesús

    2013-01-01

    Summary Background and objectives Experimental studies show that 25 (OH) vitamin D is a suppressor of renin biosynthesis and that vitamin D deficiency has been associated with CKD progression. Patients with type II diabetes and CKD have an exceptionally high rate of severe 25 (OH) vitamin D deficiency; however, it is not known whether this deficiency is a risk factor for progression of diabetic nephropathy. This study aimed to investigate whether there is an association of 25 (OH) vitamin D deficiency with disease progression in type II diabetic nephropathy. Design, setting, participants, & measurements 25 (OH) vitamin D levels were measured at baseline and 4 and 12 months in 103 patients included in a multicenter randomized controlled trial to compare the efficacy of combining an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker with the efficacy of each drug in monotherapy to slow progression of established diabetic nephropathy during 2006–2011. The primary composite endpoint was a >50% increase in baseline serum creatinine, ESRD, or death. All study participants were included in the analysis. Results Fifty-three patients (51.5%) had 25 (OH) vitamin D deficiency (<15 ng/ml). After a median follow-up of 32 months, the endpoint was reached by 23 patients with deficiency (43.4%) and 8 patients without (16%). Multivariate Cox regression analysis adjusted for urinary protein/creatinine ratio, estimated GFR, and baseline aldosterone showed that 25 (OH) vitamin D deficiency was associated with the primary endpoint (hazard ratio, 2.88; 95% confidence interval, 1.84 to 7.67; P=0.04). Conclusions These results show that 25 (OH) vitamin D deficiency is independently associated with a higher risk of the composite outcome in patients with type II diabetic nephropathy. PMID:24135218

  20. Intravenous urography with iopamidol in children with reflux and obstructive nephropathy: effects on glomerular and tubular functions and the renin-angiotensin-aldosterone system.

    PubMed

    Bosio, M; Bissoli, F; Vignati, G; Fiori, M G

    1990-05-01

    Twenty-seven children [2 with chronic renal failure (CRF)] with reflux or obstructive nephropathy underwent intravenous urography with iopamidol 370, a nonionic contrast medium 1 (CM), osmolality 796 mosmol/kg, for renal growth evaluation. Mean iopamidol dosing was 1.69 ml/kg (range 1.22-2.42); the 2 children with CRF received 2 and 2.42 ml/kg respectively. One hour after infusion a significant decrease in haematocrit, haemoglobin, plasma sodium (Na+), chloride (Cl-), renin activity and aldosterone was observed, consistent with a possible plasma volume expansion due to the slightly hypertonic CM. At the same time there was a significant increase in fractional excretion of Na+, Cl- and potassium, probably due to the haemodynamic effects and tubular response to a substance acting as on osmotic diuretic. The -24 to +48 h monitoring of albuminuria, beta-2-microglobulin excretion, and in 4 children excretion of N-acetyl-beta-glucosaminidase and alanine-aminopeptidase did not show any relevant nephrotoxicity. No untoward effect of clinical relevance was observed.

  1. The effects of blood pressure and the renin-angiotensin-aldosterone system on regional cerebral blood flow and cognitive impairment in dialysis patients.

    PubMed

    Kobayashi, Shuzo; Mochida, Yasuhiro; Ishioka, Kunihiro; Oka, Machiko; Maesato, Kyouko; Moriya, Hidekazu; Hidaka, Sumi; Ohtake, Takayasu

    2014-07-01

    Cognitive dysfunction is prevalent in chronic kidney disease patients. Little is known about the relationship between the regional cerebral blood flow (rCBF) and cognitive function in hemodialysis (HD) patients. We used quantitative single-photon emission-computed tomography (SPECT) to determine whether rCBF decreased in these patients. Fifty-four consecutive HD patients who were able to visit the hospital unassisted and had no history of stroke underwent cognitive assessment based on the Mini Mental State Examination (MMSE). Using quantitative image-analysis software, the SPECT imaging data were used to compare rCBF in HD patients and age-matched healthy controls. Thirty-four patients (63%) had MMSE scores ⩾28 (non-dementia). Regarding the extent of decreased rCBF in HD patients compared with rCBF in normal control patients, SPECT demonstrated significant rCBF decreases in all patients. rCBF in the perfusion area of the middle cerebral artery was significantly more decreased than in other areas. Multiple logistic regression analysis demonstrated that the presence or absence of a previous history of percutaneous coronary intervention, drug therapy with angiotensin II receptor antagonists and diastolic blood pressure (DBP) were independent risk factors for the extent of decreased rCBF. Regarding the severity of decreased rCBF, stepwise multiple regression analysis indicated that HD duration and systolic blood pressure (mm Hg) were chosen. In conclusion, rCBF decreased in all HD patients studied, irrespective of their clinical symptoms or MMSE scores. Blood pressure was an independent risk factor affecting the extent of decreased rCBF.

  2. Dual schedule ignition system

    SciTech Connect

    Remmers, G.M.

    1991-08-13

    This patent describes a time base generator for an ignition system of an internal combustion engine having a crankshaft. It comprises an encoder disk which rotates synchronously with the crankshaft of the engine and includes a plurality of timing features of a predetermined width which are at fixed locations relative to the crankshaft and includes at least one synchronizing feature which is at a fixed location relative to the crankshaft and to at least one of the timing features; detector means for detecting the presence or absence of the timing features and the at least one synchronizing feature and for generating digital signals representative thereof; and pulse generating means for generating a first pulse train from the trailing edge of each timing feature represented in the digital signal and for generating a second pulse train from the leading edge of each timing feature represented in the digital signal whereby the pulses of the second pulse train are advanced from the pulses of the first pulse train by a predetermined angular rotation of the crankshaft determined by the width of each timing feature.

  3. Dual mode nuclear rocket system applications.

    NASA Technical Reports Server (NTRS)

    Boretz, J. E.; Bell, J. M.; Plebuch, R. K.; Priest, C. C.

    1972-01-01

    Mission areas where the dual-mode nuclear rocket system is superior to nondual-mode systems are demonstrated. It is shown that the dual-mode system is competitive with the nondual-mode system even for those specific missions and particular payload configurations where it does not have a clear-cut advantage.

  4. Does concurrent renin-angiotensin-aldosterone blockade in (older) chronic kidney disease patients play a role in the acute renal failure epidemic in US hospitalized patients?--Three cases of severe acute renal failure encountered in a northwestern Wisconsin Nephrology practice.

    PubMed

    Onuigbo, Macaulay A C

    2009-10-01

    Following the publication of several large multicenter randomized placebo-controlled trials showing reno-protection with renin-angiotensin-aldosterone (RAAS) blockade, the last 2 decades have witnessed an escalating use of the angiotensin-converting enzyme inhibitors and the angiotensin receptor blockers. Simultaneously, we continue to experience an increasing epidemic of acute renal failure (ARF) both in community-based and in hospital-based studies. Even though other factors would be contributing to this ARF epidemic, recent published data have raised concerns of a plausible connection between increased use of the RAAS blocking agents and this ARF epidemic. In our 4-nephrologist northwestern practice, we have, in recent years, anecdotally encountered an increasing number and severity of ARF, often with hyperkalemia, sometimes requiring dialysis intervention, in patients concurrently on these agents. Over the 3-day Christmas weekend in 2007, we treated 3 cases of severe ARF (peak serum creatinine of 7.0 (3.3-9.2) mg/dL), all on RAAS blockade. Renin-angiotensin-aldosterone blockade was promptly discontinued. All patients received intravenous fluid repletion. Kidney function rapidly normalized in 2 within 1 week. One patient required hemodialysis for 14 days before his serum creatinine returned to normal after 5 weeks. All 3 patients have continued to maintain baseline serum creatinine several months later, still off RAAS blockade. The mean baseline eGFR for the 3 patients was 46 (41-51) mL/min/1.73 m(2) body surface area. This phenomenon of ARF exacerbation, which may have implications for chronic kidney disease progression to ESRD especially in the elderly, merits further study. We support the recommendation that (older, >65 years old) chronic kidney disease patients on RAAS blocking agents should have the medications temporarily suspended during any acute illness, before major surgical procedures, and before iodinated contrast or oral phosphate sodium

  5. Dual pressure displacement control system

    SciTech Connect

    Louis, J.E.; Klocke, C.C.

    1988-02-02

    This patent describes a dual pressure servo control system for a variable displacement hydraulic unit having displacement setting means positioned by a hydraulic servo mechanism. The hydraulic unit is provided with main loop lines at least one of which is capable of being subjected to high main loop pressure during operation of the hydraulic unit, a control line including a displacement control valve providing a controlled flow of fluid under pressure to the servo mechanism, and a source of fluid under pressure for the control line comprising a low pressure source connected to the control line through a check valve and high pressure source comprising of a high pressure control line connected to the control line downstream of the check valve. The high pressure control line includes a flow restriction limiting flow to the control line means and generating a significant flow induced pressure drop in the high pressure control line once movement in the servo mechanism is initiated.

  6. Lessons from the German Dual System

    ERIC Educational Resources Information Center

    Hyslop, Alisha

    2012-01-01

    Most average Americans know more about the food in Germany than the education structure, but its emphasis on a dual system of education and training has a number of insights to offer to American career and technical educators. This author had the opportunity to observe firsthand the vocational education and training system, or "VET" system as it…

  7. Nonlinear control for dual quaternion systems

    NASA Astrophysics Data System (ADS)

    Price, William D.

    The motion of rigid bodies includes three degrees of freedom (DOF) for rotation, generally referred to as roll, pitch and yaw, and 3 DOF for translation, generally described as motion along the x, y and z axis, for a total of 6 DOF. Many complex mechanical systems exhibit this type of motion, with constraints, such as complex humanoid robotic systems, multiple ground vehicles, unmanned aerial vehicles (UAVs), multiple spacecraft vehicles, and even quantum mechanical systems. These motions historically have been analyzed independently, with separate control algorithms being developed for rotation and translation. The goal of this research is to study the full 6 DOF of rigid body motion together, developing control algorithms that will affect both rotation and translation simultaneously. This will prove especially beneficial in complex systems in the aerospace and robotics area where translational motion and rotational motion are highly coupled, such as when spacecraft have body fixed thrusters. A novel mathematical system known as dual quaternions provide an efficient method for mathematically modeling rigid body transformations, expressing both rotation and translation. Dual quaternions can be viewed as a representation of the special Euclidean group SE(3). An eight dimensional representation of screw theory (combining dual numbers with traditional quaternions), dual quaternions allow for the development of control techniques for 6 DOF motion simultaneously. In this work variable structure nonlinear control methods are developed for dual quaternion systems. These techniques include use of sliding mode control. In particular, sliding mode methods are developed for use in dual quaternion systems with unknown control direction. This method, referred to as self-reconfigurable control, is based on the creation of multiple equilibrium surfaces for the system in the extended state space. Also in this work, the control problem for a class of driftless nonlinear systems is

  8. The sympathetic nervous system and heart failure.

    PubMed

    Zhang, David Y; Anderson, Allen S

    2014-02-01

    Heart failure (HF) is a syndrome characterized by upregulation of the sympathetic nervous system and abnormal responsiveness of the parasympathetic nervous system. Studies in the 1980s and 1990s demonstrated that inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors improved symptoms and mortality in HF resulting from systolic dysfunction, thus providing a framework to consider the use of β-blockers for HF therapy, contrary to the prevailing wisdom of the time. Against this backdrop, this article reviews the contemporary understanding of the sympathetic nervous system and the failing heart.

  9. 14 CFR 29.399 - Dual control system.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Strength Requirements Control Surface and System Loads § 29.399 Dual control system. Each dual primary flight control system must be able to withstand the loads that... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Dual control system. 29.399 Section...

  10. 14 CFR 27.399 - Dual control system.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... STANDARDS: NORMAL CATEGORY ROTORCRAFT Strength Requirements Control Surface and System Loads § 27.399 Dual control system. Each dual primary flight control system must be designed to withstand the loads that... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Dual control system. 27.399 Section...

  11. 14 CFR 27.399 - Dual control system.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... STANDARDS: NORMAL CATEGORY ROTORCRAFT Strength Requirements Control Surface and System Loads § 27.399 Dual control system. Each dual primary flight control system must be designed to withstand the loads that... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Dual control system. 27.399 Section...

  12. 14 CFR 27.399 - Dual control system.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... STANDARDS: NORMAL CATEGORY ROTORCRAFT Strength Requirements Control Surface and System Loads § 27.399 Dual control system. Each dual primary flight control system must be designed to withstand the loads that... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Dual control system. 27.399 Section...

  13. 14 CFR 29.399 - Dual control system.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Strength Requirements Control Surface and System Loads § 29.399 Dual control system. Each dual primary flight control system must be able to withstand the loads that... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Dual control system. 29.399 Section...

  14. 14 CFR 29.399 - Dual control system.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Strength Requirements Control Surface and System Loads § 29.399 Dual control system. Each dual primary flight control system must be able to withstand the loads that... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Dual control system. 29.399 Section...

  15. 14 CFR 29.399 - Dual control system.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Strength Requirements Control Surface and System Loads § 29.399 Dual control system. Each dual primary flight control system must be able to withstand the loads that... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Dual control system. 29.399 Section...

  16. 14 CFR 27.399 - Dual control system.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... STANDARDS: NORMAL CATEGORY ROTORCRAFT Strength Requirements Control Surface and System Loads § 27.399 Dual control system. Each dual primary flight control system must be designed to withstand the loads that... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Dual control system. 27.399 Section...

  17. Satellite dual antenna pointing system

    NASA Technical Reports Server (NTRS)

    Keigler, John E. (Inventor); Hartshorne, Frank A. (Inventor)

    1986-01-01

    A satellite antenna pointing system for separately pointing separated transmit and receive high gain antenna systems includes means for separately and sequentially applying a beacon signal to the transmit and receive antenna systems and a broad beam width antenna which has a coverage area greater than the overall coverage region of the spot beam antenna systems. The system includes ground stations located at or near the periphery of the overall coverage region adapted to receive these beacon signals. At a central control station these beacon signals are compared to provide first signals proportional to the ratio of said beacon signals received from said transmit antenna system and said broad beam width antenna and second signals proportional to the ratio of said beacon signals received from said satellite receive antenna system and said broad beam width antenna. The central station generates from said first signals transmit antenna control signals which are sent to the satellite to control the orientation of said transmit antenna system. Likewise, the central control station generates from the second signals receiver antenna control signals which are applied to the satellite to control the orientation of the satellite receive antenna system.

  18. Systemic vasculitis: a dual diagnosis?

    PubMed

    Gil, Eliza; Lutalo, Pamela; D'Cruz, David

    2011-12-02

    The authors describe a 25-year-old male with systemic vasculitis fulfilling the American College of Rheumatology classification criteria for both granulomatosis with polyangiitis (Wegener's granulomatosis) and polyarteritis nodosa. The patient was diagnosed with granulomatosis with polyangiitis following a mediastinal biopsy which revealed necrotising granulomas of the large airways, a positive cytoplasmic antineutrophil cytoplasmic antibodies and high antiproteinase 3 antibody titre. He then developed acute right-sided abdominal and testicular pain as well as areas of hyperaesthesia and parasthesiae on both lower limbs. He was found to have focal crescentic glomerulonephritis and mononeuritis multiplex, in keeping with his diagnosis of granulomatosis with polyangiitis, as well as two areas of infarction in his right testicle and multiple aneurysms of his hepatic and right renal arteries, more typical of polyarteritis nodosa. His symptoms developed 6 weeks after hepatitis B vaccination, which may have played an aetiological role.

  19. Dual liquid and gas chromatograph system

    DOEpatents

    Gay, Don D.

    1985-01-01

    A chromatographic system that utilizes one detection system for gas chromatographic and micro-liquid chromatographic determinations. The detection system is a direct-current, atmospheric-pressure, helium plasma emission spectrometer. The detector utilizes a non-transparent plasma source unit which contains the plasma region and two side-arms which receive effluents from the micro-liquid chromatograph and the gas chromatograph. The dual nature of this chromatographic system offers: (1) extreme flexibility in the samples to be examined; (2) extremely low sensitivity; (3) element selectivity; (4) long-term stability; (5) direct correlation of data from the liquid and gas samples; (6) simpler operation than with individual liquid and gas chromatographs, each with different detection systems; and (7) cheaper than a commercial liquid chromatograph and a gas chromatograph.

  20. Dual liquid and gas chromatograph system

    DOEpatents

    Gay, D.D.

    A chromatographic system is described that utilizes one detection system for gas chromatographic and micro-liquid chromatographic determinations. The detection system is a direct-current, atmospheric-pressure, helium plasma emission spectrometer. The detector utilizes a nontransparent plasma source unit which contains the plasma region and two side-arms which receive effluents from the micro-liquid chromatograph and the gas chromatograph. The dual nature of this chromatographic system offers: (1) extreme flexibility in the samples to be examined; (2) extreme low sensitivity; (3) element selectivity; (4) long-term stability; (5) direct correlation of data from the liquid and gas samples; (6) simpler operation than with individual liquid and gas chromatographs, each with different detection systems; and (7) cheaper than a commercial liquid chromatograph and a gas chromatograph.

  1. Dual-keel electrodynamic Maglev system

    SciTech Connect

    He, Jianliang; Rote, D.M.; Wang, Zian; Coffey, H.T.

    1995-12-31

    This paper introduces a new concept for an electrodynamic-suspension maglev system that has a dual-keel arrangement. Each keel consists of a row of superconducting magnets aboard the vehicle. The keels move in troughs in the guideway that are each lined with pairs of figure-eight-shaped null-flux coils. Each pair of null-flux coils is cross-connected to produce null-flux suspension and guidance force. The cross-connected figure-eight null-flux coils in each trough are also energized by a three-phase power supply to produce propulsive force. Preliminary analysis shows that the new system has many advantages over other EDS systems in terms of system performance and dynamic stability.

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

    PubMed

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

    2016-05-18

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

  3. Pre- and/or Intra-Operative Prescription of Diuretics, but Not Renin-Angiotensin-System Inhibitors, Is Significantly Associated with Acute Kidney Injury after Non-Cardiac Surgery: A Retrospective Cohort Study

    PubMed Central

    Tagawa, Miho; Ogata, Ai; Hamano, Takayuki

    2015-01-01

    Background and Objectives Pre- and/or intra-operative use of diuretics, angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARB) constitutes a potentially modifiable risk factor for postoperative acute kidney injury (AKI). It has been studied whether use of these drugs predicts AKI after cardiac surgery. The objective of this study was to examine whether administration of these agents was independently associated with AKI after non-cardiac surgery. Design, Setting, Participants, and Measurements This was a retrospective observational study. Inclusion criteria were adult patients (age ≥ 18) who underwent non-cardiac surgery under general anesthesia from 2007 to 2009 at Kyoto Katsura Hospital. Exclusion criteria were urological surgery, missing creatinine values, and preoperative dialysis. The exposures of interest were pre- and/or intra-operative use of diuretics or ACE-I/ARB. Outcome variables were postoperative AKI as defined by the AKI Network (increase in creatinine ≥ 0.3 mg/dL or 150% within 48 hours, or urine output < 0.5 ml/kg/hour for > 6 hours). Multivariable logistic regression analyses were conducted and adjusted for potential confounders. Propensity scores (PS) for receiving diuretics or ACE-I/ARB therapy were estimated and PS adjustment, PS matching, and inverse probability weighting were performed. Results There were 137 AKI cases (5.0%) among 2,725 subjects. After statistical adjustment for patient and surgical characteristics, odds (95% CI) of postoperative AKI were 2.07 (1.10-3.89) (p = 0.02) and 0.89 (0.56-1.42) (p = 0.63) in users of diuretics and ACE-I/ARB, respectively, compared with non-users. PS adjustment, PS matching, and inverse probability weighting yielded similar results. The effect size of diuretics was significantly greater in the patients with lower propensity for diuretic use (p for interaction < 0.1). Conclusions Prescription of diuretics, but not ACE-I/ARB, was independently associated with postoperative AKI after non-cardiac surgery, especially in patients with low propensity for diuretic use. It might be reasonable to withhold preoperative diuretics in these patients. PMID:26146836

  4. Effect of Renin-Angiotensin-Aldosterone System Inhibition, Dietary Sodium Restriction, and/or Diuretics on Urinary Kidney Injury Molecule 1 Excretion in Nondiabetic Proteinuric Kidney Disease: A Post Hoc Analysis of a Randomized Controlled Trial

    PubMed Central

    Waanders, Femke; Vaidya, Vishal S.; van Goor, Harry; Leuvenink, Henri; Damman, Kevin; Hamming, Inge; Bonventre, Joseph V.; Vogt, Liffert; Navis, Gerjan

    2012-01-01

    Background Tubulointerstitial damage plays an important role in chronic kidney disease (CKD) with proteinuria. Urinary kidney injury molecule 1 (KIM-1) reflects tubular KIM-1 and is considered a sensitive biomarker for early tubular damage. We hypothesized that a decrease in proteinuria by using therapeutic interventions is associated with decreased urinary KIM-1 levels. Study Design Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover trial. Setting & Participants 34 proteinuric patients without diabetes from our outpatient renal clinic. Intervention Stepwise 6-week interventions of losartan, sodium restriction (low-sodium [LS] diet), their combination, losartan plus hydrochlorothiazide (HCT), and the latter plus an LS diet. Outcomes & Measurements Urinary excretion of KIM-1, total protein, and N-acetyl-β-D-glucosaminidase (NAG) as a positive control for tubular injury. Results Mean baseline urine protein level was 3.8 ± 0.4 (SE) g/d, and KIM-1 level was 1,706 ± 498 ng/d (increased compared with healthy controls; 74 ng/d). KIM-1 level was decreased by using placebo/LS (1,201 ± 388 ng/d; P = 0.04), losartan/high sodium (1,184 ± 296 ng/d; P = 0.09), losartan/LS (921 ± 176 ng/d; P = 0.008), losartan/high sodium plus HCT (862 ± 151 ng/d; P = 0.008) and losartan/LS plus HCT (743 ± 170 ng/d; P = 0.001). The decrease in urinary KIM-1 levels paralleled the decrease in proteinuria (R = 0.523; P < 0.001), but not blood pressure or creatinine clearance. 16 patients reached target proteinuria with protein less than 1 g/d, whereas KIM-1 levels normalized in only 2 patients. Urinary NAG level was increased at baseline and significantly decreased during the treatment periods of combined losartan plus HCT only. The decrease in urinary NAG levels was not closely related to proteinuria. Limitations Post hoc analysis. Conclusions Urinary KIM-1 level was increased in patients with nondiabetic CKD with proteinuria and decreased in parallel with proteinuria by using losartan, sodium restriction, their combination, losartan plus HCT, and the latter plus sodium restriction. These results are consistent with the hypothesis of amelioration of proteinuria-induced tubular damage. Long-term studies are warranted to evaluate whether targeting treatment on KIM-1 can improve outcomes in patients with CKD with proteinuria. PMID:18823687

  5. 14 CFR 25.399 - Dual control system.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... system. (a) Each dual control system must be designed for the pilots operating in opposition, using... forces specified in § 25.397(c). (b) The control system must be designed for pilot forces applied in the... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Dual control system. 25.399 Section...

  6. Dual-keel electrodynamic maglev system

    SciTech Connect

    He, J.; Wang, Z.; Rote, D.M.; Coffey, H.T.; Hull, J.R.; Mulcahy, T.M.; Cai, Y.

    1995-12-31

    A propulsion and stabilization system with a plurality of superconducting magnetic devices affixed to the dual-keels of a vehicle, where the superconducting magnetic devices produce a magnetic field when energized. The system also includes a plurality of figure-eight shaped null-flux coils affixed to opposing vertical sides of slots in a guideway. The figure-eight shaped null-flux coils are vertically oriented, laterally cross-connected in parallel, longitudinally connected in series, and continue the length of the vertical slots providing levitation and guidance force. An external power source energizes the figure-eight shaped null-flux coils to create a magnetic traveling wave that interacts with the magnetic field produced by the superconducting magnets to impart motion to the vehicle.

  7. Dual-keel electrodynamic maglev system

    DOEpatents

    He, J.L.; Wang, Z.; Rote, D.M.; Coffey, H.T.; Hull, J.R.; Mulcahy, T.M.; Cal, Y.

    1996-12-24

    A propulsion and stabilization system is disclosed with a plurality of superconducting magnetic devices affixed to the dual-keels of a vehicle, where the superconducting magnetic devices produce a magnetic field when energized. The system also includes a plurality of figure-eight shaped null-flux coils affixed to opposing vertical sides of slots in a guideway. The figure-eight shaped null-flux coils are vertically oriented, laterally cross-connected in parallel, longitudinally connected in series, and continue the length of the vertical slots providing levitation and guidance force. An external power source energizes the figure-eight shaped null-flux coils to create a magnetic traveling wave that interacts with the magnetic field produced by the superconducting magnets to impart motion to the vehicle. 6 figs.

  8. Dual-keel electrodynamic maglev system

    DOEpatents

    He, Jianliang; Wang, Zian; Rote, Donald M.; Coffey, Howard T.; Hull, John R.; Mulcahy, Thomas M.; Cal, Yigang

    1996-01-01

    A propulsion and stabilization system with a plurality of superconducting magnetic devices affixed to the dual-keels of a vehicle, where the superconducting magnetic devices produce a magnetic field when energized. The system also includes a plurality of figure-eight shaped null-flux coils affixed to opposing vertical sides of slots in a guideway. The figure-eight shaped null-flux coils are vertically oriented, laterally cross-connected in parallel, longitudinally connected in series, and continue the length of the vertical slots providing levitation and guidance force. An external power source energizes the figure-eight shaped null-flux coils to create a magnetic traveling wave that interacts with the magnetic field produced by the superconducting magnets to impart motion to the vehicle.

  9. Costs and energy efficiency of a dual-mode system

    NASA Technical Reports Server (NTRS)

    Heft, R. C.

    1977-01-01

    The life cycle costs of a dual mode system for both public and semiprivate ownership are examined, and the costs in terms of levelized required revenue per passenger mile are presented. The energy use of the dual mode vehicle is analyzed by means of a detailed vehicle simulation program for the control policy and guideway system. Several different propulsion systems are considered.

  10. Sex hormones in the cardiovascular system.

    PubMed

    dos Santos, Roger Lyrio; da Silva, Fabrício Bragança; Ribeiro, Rogério Faustino; Stefanon, Ivanita

    2014-05-01

    Gender-associated differences in the development of cardiovascular diseases have been described in humans and animals. These differences could explain the low incidence of cardiovascular disease in women in the reproductive period, such as stroke, hypertension, and atherosclerosis. The cardiovascular protection observed in females has been attributed to the beneficial effects of estrogen on endothelial function. Besides estrogen, sex hormones are able to modulate blood pressure by acting on important systems as cardiovascular, renal, and neural. They can have complementary or antagonistic actions. For example, testosterone can raise blood pressure by stimulating the renin-angiotensin-aldosterone system, whereas estrogen alone or combined with progesterone has been associated with decreased blood pressure. The effects of testosterone in the development of cardiovascular disease are contradictory. Although some researchers suggest a positive effect, others indicate negative actions of testosterone. Estrogens physiologically stimulate the release of endothelium-derived vasodilator factors and inhibit the renin-angiotensin system. Although the cardioprotective effects of estrogen are widely appreciated, little is known about the effects of progesterone, which is commonly used in hormone replacement therapy. Progesterone has both vasodilatory and vasoconstrictive effects in the vasculature, depending on the location of the vessel and the level of exposure. Nevertheless, the mechanisms through which sex hormones modulate blood pressure have not been fully elucidated. Therefore, the characterization of those could lead to a better understanding of hypertension in women and men and perhaps to improved forms of therapy.

  11. Dual power, constant speed electric motor system

    DOEpatents

    Kirschbaum, H.S.

    1984-07-31

    A dual capacity permanent split capacitor electric motor system is provided with a stator having main and auxiliary windings. The main stator winding includes two winding sections which are connected in parallel with each other and across a pair of line terminals while the auxiliary winding is connected in series with a capacitor to form a circuit branch which is connected between the line terminals for operation at a first output power level. Switching means are provided to reconnect the main stator winding sections in series with each other and in series with a second capacitor to form a circuit branch which is connected between the line terminals while the stator auxiliary winding is connected directly between the line terminals for operation at a second output power level. Automatic rotation reversal occurs when the motor switches from the first to the second output power level. 6 figs.

  12. Dual arm robotic system with sensory input

    NASA Technical Reports Server (NTRS)

    Ozguner, U.

    1987-01-01

    The need for dual arm robots in space station assembly and satellite maintainance is of increasing significance. Such robots will be in greater demand in the future when numerous tasks will be assigned to them to relieve the direct intervention of humans in space. Technological demands from these robots will be high. They will be expected to perform high speed tasks with a certain degree of autonomy. Various levels of sensing will have to be used in a sophisticated control scheme. Ongoing research in control, sensing and real-time software to produce a two-arm robotic system than can accomplish generic assembly tasks is discussed. The control hierarchy and the specific control approach are discussed. A decentralized implementation of model-reference adaptive control using Variable Structure controllers and the incorporation of tactile feedback is considered.

  13. Dual power, constant speed electric motor system

    DOEpatents

    Kirschbaum, Herbert S.

    1984-01-01

    A dual capacity permanent split capacitor electric motor system is provided with a stator having main and auxiliary windings. The main stator winding includes two winding sections which are connected in parallel with each other and across a pair of line terminals while the auxiliary winding is connected in series with a capacitor to form a circuit branch which is connected between the line terminals for operation at a first output power level. Switching means are provided to reconnect the main stator winding sections in series with each other and in series with a second capacitor to form a circuit branch which is connected between the line terminals while the stator auxiliary winding is connected directly between the line terminals for operation at a second output power level. Automatic rotation reversal occurs when the motor switches from the first to the second output power level.

  14. A Dual System Model of Preferences under Risk

    ERIC Educational Resources Information Center

    Mukherjee, Kanchan

    2010-01-01

    This article presents a dual system model (DSM) of decision making under risk and uncertainty according to which the value of a gamble is a combination of the values assigned to it independently by the affective and deliberative systems. On the basis of research on dual process theories and empirical research in Hsee and Rottenstreich (2004) and…

  15. 14 CFR 23.399 - Dual control system.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ...) Each dual control system must be designed to withstand the force of the pilots applied together, in the... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Dual control system. 23.399 Section 23.399... STANDARDS: NORMAL, UTILITY, ACROBATIC, AND COMMUTER CATEGORY AIRPLANES Structure Control Surface and...

  16. Dual-mode Continuous Arrhythmias Telemonitoring System

    NASA Astrophysics Data System (ADS)

    Amien, Magdi B. M.; Lin, Jiarui

    Coronary artery disease still remains the main cause of death. The existence of silent myocardial isocheim emphasized the need for All-day real-time monitoring. Therefore patient monitoring during normal activity has become increasingly important as a standard preventive craniological procedure for detection of cardiac Arrhythmias, transient ischemic episodes and silent myocardial ischemia. This paper deals the design and implementation of a Dual-mode, (700 m) Wireless Real-time Arrhythmias monitoring and Auto-warning System. The system consists of slave node, and master node with a PC-based Application user interface. The system operates at the license-free open frequency band 915 MHZ. The slave node is a DSP-based smart board carried by the patient; it acquires two channels of full-spectrum ECG, stores samples on a Flash memory capable of handling 1GBits of data, compress and transmits a digitally-processed cardiac heart signal each time with detected QRS synchronous pulses as transmission data packet. The master node is responsible for receiving, decompressing, and analyzing the transmitted data packets. The SRWF-501F915 integrated module realizes the data transmitting and receiving. The developed system can be configured as master-slave or Stand-Alone topology.

  17. Optical system design of dual-spectrum autocollimator

    NASA Astrophysics Data System (ADS)

    Wei, Yongjing; Wu, Yiming; Xiao, Maosen; Lu, Weiguo

    2015-10-01

    The optical system design of a new dual-spectrum autocollimator which can measure two different spatial azimuths simultaneously is proposed. According to the principle of dual-spectrum autocollimator, ZEMAX software is used to design and optimize the optical system. Since two light sources with different wavelength are used in the autocollimator, chromatic aberration is required to reduce off in the optical system design. The experimental results demonstrate that the measuring range of the dual-spectrum autocollimator is up to +/-30', the deviation is less than 1″, and the resolution can reach 0.1". The designed autocollimator can simultaneously measure two different azimuths fastly and accurately.

  18. Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors.

    PubMed

    Meredith, Erik L; Ksander, Gary; Monovich, Lauren G; Papillon, Julien P N; Liu, Qian; Miranda, Karl; Morris, Patrick; Rao, Chang; Burgis, Robin; Capparelli, Michael; Hu, Qi-Ying; Singh, Alok; Rigel, Dean F; Jeng, Arco Y; Beil, Michael; Fu, Fumin; Hu, Chii-Whei; LaSala, Daniel

    2013-12-12

    Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure-activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing's syndrome. PMID:24900631

  19. Signaling Pathways Involved in Renal Oxidative Injury: Role of the Vasoactive Peptides and the Renal Dopaminergic System

    PubMed Central

    Rukavina Mikusic, N. L.; Kravetz, M. C.; Kouyoumdzian, N. M.; Della Penna, S. L.; Rosón, M. I.; Fernández, B. E.; Choi, M. R.

    2014-01-01

    The physiological hydroelectrolytic balance and the redox steady state in the kidney are accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Angiotensin II, atrial natriuretic peptide and intrarenal dopamine play a pivotal role in this interactive network. The balance between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide, by one side, and the prooxidant effect of the renin angiotensin system, by the other side, contributes to ensuring the normal function of the kidney. Different pathological scenarios, as nephrotic syndrome and hypertension, where renal sodium excretion is altered, are associated with an impaired interaction between two natriuretic systems as the renal dopaminergic system and atrial natriuretic peptide that may be involved in the pathogenesis of renal diseases. The aim of this review is to update and comment the most recent evidences about the intracellular pathways involved in the relationship between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide and the prooxidant effect of the renin angiotensin system in the pathogenesis of renal inflammation. PMID:25436148

  20. Technology, Applications, and Process Challenges of Dual Chamber Systems.

    PubMed

    Werk, Tobias; Ludwig, Imke S; Luemkemann, Joerg; Mahler, Hanns-Christian; Huwyler, Joerg; Hafner, Mathias

    2016-01-01

    Dual-chamber systems provide an option as a drug and device combination product, when home care and emergency lyophilized products are intended. Nevertheless, until today, there are only a few products on the market, due to the challenges and limitations in manufacturability, product formulation, and product stability in a dual-chamber configuration, as well as economic considerations. This review serves to describe currently available dual-chamber systems and to discuss factors to be considered for appropriate selection and establishing fill-finish processes. PMID:26852837

  1. TESTING OF THE DUAL ROTARY FILTER SYSTEM

    SciTech Connect

    Herman, D.; Fowley, M.; Stefanko, D.

    2011-08-29

    The Savannah River National Laboratory (SRNL) installed and tested two hydraulically connected SpinTek rotary microfilter (RMF) units to determine the behavior of a multiple filter system. Both units were successfully controlled by a control scheme written in DELTA-V architecture by Savannah River Remediation (SRR) Process Control Engineering personnel. The control system was tuned to provide satisfactory response to changing conditions during the operation of the multi-filter system. Stability was maintained through the startup and shutdown of one of the filter units while the second was still in operation. The installation configuration originally proposed by the Small Colum Ion Exchange (SCIX) project of independent filter and motor mountings may be susceptible to vibration. Significant stiffening of the filter and motor mounts was required to minimize the vibration. Alignment of the motor to the filter was a challenge in this test configuration. The deployment configuration must be easy to manipulate and allow for fine adjustment. An analysis of the vibration signature of the test system identified critical speeds. Whether it corresponds to the resonance frequency of a rotor radial vibration mode that was excited by rotor unbalance is uncertain based upon the measurements. A relative motion series should be completed on the filter with the final shaft configuration to determine if the resonances exist in the final filter design. The instrumentation selected for deployment, including the concentrate discharge control valve and flow meters, performed well. Automation of the valve control integrated well with the control scheme and when used in concert with the other control variables, allowed automated control of the dual RMF system. The one area of concern with the instrumentation was the condition resulting when the filtrate flow meter operated with less than three gpm. This low flow was at the lower range of performance for the flow meter. This should not be

  2. Counter sniper: a localization system based on dual thermal imager

    NASA Astrophysics Data System (ADS)

    He, Yuqing; Liu, Feihu; Wu, Zheng; Jin, Weiqi; Du, Benfang

    2010-11-01

    Sniper tactics is widely used in modern warfare, which puts forward the urgent requirement of counter sniper detection devices. This paper proposed the anti-sniper detection system based on a dual-thermal imaging system. Combining the infrared characteristics of the muzzle flash and bullet trajectory of binocular infrared images obtained by the dual-infrared imaging system, the exact location of the sniper was analyzed and calculated. This paper mainly focuses on the system design method, which includes the structure and parameter selection. It also analyzes the exact location calculation method based on the binocular stereo vision and image analysis, and give the fusion result as the sniper's position.

  3. Design of an ultra-thin dual band infrared system

    NASA Astrophysics Data System (ADS)

    Du, Ke; Cheng, Xuemin; Lv, Qichao; Hu, YiFei

    2014-11-01

    The ultra-thin imaging system using reflective multiple-fold structure has smaller volume and less weight while maintaining high resolution compared with conventional optical systems. The multi-folded approach can significantly extend focal distance within wide spectral range without incurring chromatic aberrations. In this paper, we present a dual infrared imaging system of four-folded reflection with two air-spaced concentric reflective surfaces. The dual brand IR system has 107mm effective focal length, 0.7NA, +/-4° FOV, and 50mm effective aperture with 80mm outer diameter into a 25mm total thickness, which spectral response is 3~12μm.

  4. Estimating the weight of generally configured dual wing systems

    NASA Technical Reports Server (NTRS)

    Cronin, D. L.; Somnay, R. J.

    1985-01-01

    Formulas available for the weight estimation of monoplane wings cannot be said to be appropriate for the estimation of generally configured dual wing systems. In the present paper a method is described which simultaneously generates a structural weight estimate and a fully stressed, quasi-optimal structure for a model of a dual wing system. The method is fast and inexpensive. It is ideally suited to preliminary design. To illustrate the method, a dual wing system and a conventional wing system are sized. Numerical computation is shown to be suitably fast for both cases and, for both cases, convergence to a final configuration is shown to be quite rapid. To illustrate the validity of the method, a conventional wing is sized and its weight obtained by the present method is compared to its weight determined by a reputable weight estimation formula. The results are shown to be very close.

  5. Design of a dynamic dual-foveated imaging system.

    PubMed

    Du, Xiaoyu; Chang, Jun; Zhang, Yunqiang; Wang, Xi; Zhang, Bochuan; Gao, Lei; Xiao, Liping

    2015-10-01

    A new kind of dynamic dual-foveated imaging system in the infrared band is designed and optimized in this paper. Dual-foveated imaging refers to the variation in spatial resolution at the two selected fields across the image. Such variable resolution imaging system is suitable for a variety of applications including monitoring, recognition, and remote operation of unmanned aerial vehicle. In this system, a transmissive spatial light modulator (SLM) is used as an active optical element which is located near the image plane instead of pupil plane creatively in order to divide the two selected fields. PMID:26480118

  6. 40. View of dual projector system located in MWOC facility ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    40. View of dual projector system located in MWOC facility in transmitter building no. 102 by Bessler Company. System used to project images in MWOC on backlit screen system with fiber optic electro/mechanical system linked to computer output to indicate information on screen linked with display from projector system. - Clear Air Force Station, Ballistic Missile Early Warning System Site II, One mile west of mile marker 293.5 on Parks Highway, 5 miles southwest of Anderson, Anderson, Denali Borough, AK

  7. Special Education Teacher Preparation in Singapore's Dual Education System

    ERIC Educational Resources Information Center

    Walker, Zachary

    2016-01-01

    Global comparisons of teacher education programs should start with an understanding of the school systems that teachers are being prepared for in their local contexts. The purpose of this article is to describe Singapore's dual education system as well as teacher preparation in a country that educates many students with disabilities in a separate…

  8. Solution of a system of dual integral equations.

    NASA Technical Reports Server (NTRS)

    Buell, J.; Kagiwada, H.; Kalaba, R.; Ruspini, E.; Zagustin, E.

    1972-01-01

    The solution of a presented system of differential equations with initial values is shown to satisfy a system of dual integral equations of a type appearing in the study of axisymmetric problems of potential theory. Of practical interest are possible applications in biomechanics, particularly, for the case of trauma due to impact.

  9. Dual-Use system architecture for a space situational awareness system in Japan

    NASA Astrophysics Data System (ADS)

    Otani, Y.; Kohtake, N.; Ohkami, Y.

    The use of outer space plays a vital role in both defense and civil fields. Since the separation of space activities between civil and defense applications is extremely inefficient, the Dual-Use concept has been considered fundamental for promoting the effective use of space. To the best of the authors' knowledge, most previous studies on Dual-Use focused on the technological aspects, and very few on a system engineering approach to Dual-Use. This left some important issues untouched such as the operational aspects of a system of systems, which need to be understood in a more generic context. This paper presents the results of a conceptual study, system design and management analysis of Dual-Use system architecture. First, an outline of the Dual-Use concept will be described and a definition of Dual-Use given. The effectiveness of applying the Dual-Use system concept to Space Situational Awareness (SSA) for both defense and civil users as a system of systems will then be discussed and investigated with a stakeholders analysis, context diagram and design structure matrix method. It has demonstrated that there is a need for a Dual-Use SSA Data Center which works as a binder between defense and civil systems as well as a data policy for constructing a Dual-Use SSA system.

  10. Aerodynamic-structural analysis of dual bladed helicopter systems

    NASA Technical Reports Server (NTRS)

    Selberg, B. P.; Cronin, D. L.; Rokhsaz, K.; Dykman, J. R.; Yager, C. J.

    1980-01-01

    The aerodynamic and structural feasibility of the birotor blade concept is assessed. The inviscid flow field about the dual bladed rotor was investigated to determine the aerodynamic characteristics for various dual rotor blade placement combinations with respect to blade stagger, gap, and angle of attack between the two blades. The boundary layer separation on the rotors was studied and three dimensional induced drag calculations for the dual rotor system are presented. The thrust and power requirements of the rotor system were predicted. NASTRAN, employed as the primary modeling tool, was used to obtain a model for predicting in plane bending, out of plane bending, and the torsional behavior of the birotors. Local hub loads, blade loads, and the natural frequencies for the birotor configuration are discussed.

  11. Combustion system for dual fuel engine

    SciTech Connect

    Schaub, F.S.; Smith, J.G.

    1990-10-30

    This patent describes in an dual gas-liquid fuel four cycle engine having cylinders and wherein each cylinder is operatively connected thereto and each cylinder has a piston, two inlet valves, two exhaust valves and a first liquid fuel injector. It comprises: at least one fuel torch cell operatively connected to at least one cylinder, the torch cell having a torch cell nozzle at one end thereof and the other end having appropriate means to connect the torch cell to a fuel supply, a second fuel injector mounted in the torch cell at a predetermined angle to an axis of the torch cell, the torch cell defining an auto-ignition chamber, the second fuel injector being in operative communication with the auto-ignition chamber by an injector nozzle passageway, the injector nozzle passageway entering the auto-ignition chamber at a predetermined angle relative to the axis, and a torch nozzle passage connecting the auto-ignition chamber with the cylinder at a predetermined angle to a top inner portion of a cylinder head.

  12. 14 CFR 27.399 - Dual control system.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Dual control system. 27.399 Section 27.399 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... result when pilot forces of 0.75 times those obtained under § 27.395 are applied— (a) In opposition;...

  13. 14 CFR 23.399 - Dual control system.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Dual control system. 23.399 Section 23.399 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS...) 0.75 times those obtained under § 23.395; or (2) The minimum forces specified in § 23.397(b)....

  14. 14 CFR 29.399 - Dual control system.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Dual control system. 29.399 Section 29.399 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... result when pilot forces not less than 0.75 times those obtained under § 29.395 are applied— (a)...

  15. 14 CFR 25.399 - Dual control system.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Dual control system. 25.399 Section 25.399 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... individual pilot forces not less than— (1) 0.75 times those obtained under § 25.395; or (2) The...

  16. Height estimation improvement via baseline calibration for a dual-pass dual-antenna ground-mapping IFSAR system

    NASA Astrophysics Data System (ADS)

    Martinez, Ana; Doerry, Armin W.; Bickel, Douglas L.; Jamshidi, Mohammed

    2003-11-01

    Data collection for interferometric synthetic aperture radar (IFSAR) mapping systems currently utilize two operation modes. A single-antenna, dual-pass IFSAR operation mode is the first mode in which a platform carrying a single antenna traverses a flight path by the scene of interest twice collecting data. A dual-antenna, single-pass IFSAR operation mode is the second mode where a platform possessing two antennas flies past the scene of interest collecting data. There are advantages and disadvantages associated with both of these data collection modes. The single-antenna, dual-pass IFSAR operation mode possesses an imprecise knowledge of the antenna baseline length but allows for large antenna baseline lengths. This imprecise antenna baseline length knowledge lends itself to inaccurate target height scaling. The dual-antenna, one-pass IFSAR operation mode allows for a precise knowledge of the limited antenna baseline length but this limited baseline length leads to increased target height noise. This paper presents a new, innovative dual-antenna, dual-pass IFSAR operation mode which overcomes the disadvantages of the two current IFSAR operation modes. Improved target height information is now obtained with this new mode by accurately estimating the antenna baseline length between the dual flight passes using the data itself. Consequently, this new IFSAR operation mode possesses the target height scaling accuracies of the dual-antenna, one-pass operation mode and the height-noise performance of the one-antenna, dual-pass operation mode.

  17. Height estimation improvement via baseline calibration for a dual-pass, dual-antenna ground mapping IFSAR system.

    SciTech Connect

    Martinez, Ana; Jamshidi, Mohammad; Bickel, Douglas Lloyd; Doerry, Armin Walter

    2003-07-01

    Data collection for interferometric synthetic aperture radar (IFSAR) mapping systems currently utilize two operation modes. A single-antenna, dual-pass IFSAR operation mode is the first mode in which a platform carrying a single antenna traverses a flight path by the scene of interest twice collecting data. A dual-antenna, single-pass IFSAR operation mode is the second mode where a platform possessing two antennas flies past the scene of interest collecting data. There are advantages and disadvantages associated with both of these data collection modes. The single-antenna, dual-pass IFSAR operation mode possesses an imprecise knowledge of the antenna baseline length but allows for large antenna baseline lengths. This imprecise antenna baseline length knowledge lends itself to inaccurate target height scaling. The dual-antenna, one-pass IFSAR operation mode allows for a precise knowledge of the limited antenna baseline length but this limited baseline length leads to increased target height noise. This paper presents a new, innovative dual-antenna, dual-pass IFSAR operation mode which overcomes the disadvantages of the two current IFSAR operation modes. Improved target height information is now obtained with this new mode by accurately estimating the antenna baseline length between the dual flight passes using the data itself. Consequently, this new IFSAR operation mode possesses the target height scaling accuracies of the dual-antenna, one-pass operation mode and the height-noise performance of the one-antenna, dual-pass operation mode.

  18. 46 CFR 111.05-29 - Dual voltage direct current systems.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 4 2013-10-01 2013-10-01 false Dual voltage direct current systems. 111.05-29 Section... Dual voltage direct current systems. Each dual voltage direct current system must have a suitably sensitive ground detection system which indicates current in the ground connection, has a range of at...

  19. 46 CFR 111.05-29 - Dual voltage direct current systems.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 4 2011-10-01 2011-10-01 false Dual voltage direct current systems. 111.05-29 Section... Dual voltage direct current systems. Each dual voltage direct current system must have a suitably sensitive ground detection system which indicates current in the ground connection, has a range of at...

  20. 46 CFR 111.05-29 - Dual voltage direct current systems.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 4 2014-10-01 2014-10-01 false Dual voltage direct current systems. 111.05-29 Section... Dual voltage direct current systems. Each dual voltage direct current system must have a suitably sensitive ground detection system which indicates current in the ground connection, has a range of at...

  1. 46 CFR 111.05-29 - Dual voltage direct current systems.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 4 2010-10-01 2010-10-01 false Dual voltage direct current systems. 111.05-29 Section... Dual voltage direct current systems. Each dual voltage direct current system must have a suitably sensitive ground detection system which indicates current in the ground connection, has a range of at...

  2. 46 CFR 111.05-29 - Dual voltage direct current systems.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 4 2012-10-01 2012-10-01 false Dual voltage direct current systems. 111.05-29 Section... Dual voltage direct current systems. Each dual voltage direct current system must have a suitably sensitive ground detection system which indicates current in the ground connection, has a range of at...

  3. Automatic target locating system through cooperative dual-field imaging

    NASA Astrophysics Data System (ADS)

    Huang, Kun; He, Yuqing; Hou, Boyan; Wei, Shan; Wang, Siyuan

    2015-04-01

    This paper proposes an automatic targeting locating system based on dual-field imaging to improve the stability of light weapons. The system consists of a wide field of view (WFOV) camera and a narrow field of view (NFOV) camera. The WFOV camera searches the pedestrian in the scenery, the other camera tracks the pedestrian and aims it accurately. Video signal is send to the processing unit PC and control signal is send back to the imaging system. This automatic target tracking algorithm is integrated by Adaboost and Median-Flow algorithm. It is used to track the pedestrians and locate the head of the target. Experiment results show that the dual-field imaging system and proposed algorithm has robust target tracking performance.

  4. Kinetics of conversion of two dual-cured adhesive systems.

    PubMed

    Faria-e-Silva, André Luis; Casselli, Denise Sá Maia; Lima, Giana Silveira; Ogliari, Fabrício Aulo; Piva, Evandro; Martins, Luis Roberto Marcondes

    2008-09-01

    The aim of this study was to evaluate the kinetics of conversion of Scotchbond Multi-purpose Plus (3M ESPE, St Paul, MN) and Prime&Bond NT (Dentsply De Trey, Konstanz, Germany) used in light-cured, self-cured, or dual-cured versions. The adhesive systems were used in the light-cured version (without the use of chemical initiator) or mixed with its respective chemical initiator either with light activation (dual-cured) or not (self-cured). The degree of conversion (DC) was monitored as a function of time during 5 minutes with a Fourier transform infrared spectrometer equipped with an attenuated total reflectance device. Light-cured and dual-cured modes of Scotchbond Multi-purpose Plus presented the highest DC at 5 minutes. The addition of the self-cure activator (dual-cured mode) to Prime&Bond NT reduced the DC. For the self-cured versions, only the Scotchbond Multi-purpose Plus presented any polymerization reaction at 5 minutes. For the two bonding systems tested, it appears that light curing of the adhesive is important in order to reach a high DC in the first moments after the bonding procedure.

  5. Using dual-purpose crops in sheep-grazing systems.

    PubMed

    Dove, Hugh; Kirkegaard, John

    2014-05-01

    The utilisation of dual-purpose crops, especially wheat and canola grown for forage and grain production in sheep-grazing systems, is reviewed. When sown early and grazed in winter before stem elongation, later-maturing wheat and canola crops can be grazed with little impact on grain yield. Recent research has sought to develop crop- and grazing-management strategies for dual-purpose crops. Aspects examined have been grazing effects on crop growth, recovery and yield development along with an understanding of the grazing value of the crop fodder, its implications for animal nutrition and grazing management to maximise live-weight gain. By alleviating the winter 'feed gap', the increase in winter stocking rate afforded by grazing crops allows crop and livestock production to be increased simultaneously on the same farm. Integration of dual-purpose wheat with canola on mixed farms provides further systems advantages related to widened operational windows, weed and disease control and risk management. Dual-purpose crops are an innovation that has potential to assist in addressing the global food-security challenge. PMID:24323974

  6. Dual band infrared picture-in-picture systems

    NASA Astrophysics Data System (ADS)

    Vizgaitis, Jay N.; Hastings, Arthur

    2013-06-01

    Dual band infrared focal plane arrays (FPA) are designed to act as two independent focal planes located at a common image plane which detects both the mid-wave infrared and the long-wave infrared images. The imagery produced is simultaneous and separable for the two bands. Systems utilizing these focal planes have often been designed to operate the same way as single band infrared sensors, except that two images of the same scene but different spectral bands are simultaneously captured, and displayed independently or as a fused image. An alternative method of exploiting dual band FPA is to utilize the dual band nature of the focal plane to simultaneously view different scenes. It is feasible to provide a picture-in-picture capability where one spectral band views a narrow field of view (FOV) to identify targets while the other spectral band images the wide FOV to provide situational awareness. We explore this capability, including design concepts and issues associated with the development of a dual band picture-in-picture infrared system.

  7. Using dual-purpose crops in sheep-grazing systems.

    PubMed

    Dove, Hugh; Kirkegaard, John

    2014-05-01

    The utilisation of dual-purpose crops, especially wheat and canola grown for forage and grain production in sheep-grazing systems, is reviewed. When sown early and grazed in winter before stem elongation, later-maturing wheat and canola crops can be grazed with little impact on grain yield. Recent research has sought to develop crop- and grazing-management strategies for dual-purpose crops. Aspects examined have been grazing effects on crop growth, recovery and yield development along with an understanding of the grazing value of the crop fodder, its implications for animal nutrition and grazing management to maximise live-weight gain. By alleviating the winter 'feed gap', the increase in winter stocking rate afforded by grazing crops allows crop and livestock production to be increased simultaneously on the same farm. Integration of dual-purpose wheat with canola on mixed farms provides further systems advantages related to widened operational windows, weed and disease control and risk management. Dual-purpose crops are an innovation that has potential to assist in addressing the global food-security challenge.

  8. The German Dual Apprenticeship System: An Analysis of Its Evolution and Present Challenges.

    ERIC Educational Resources Information Center

    Tremblay, Diane-Gabrielle; Le Bot, Irene

    The evolution of Germany's dual apprenticeship system and the challenges now facing it were reviewed. The following topics were considered: (1) the progression from craft guilds to vocational training; (2) the history of Germany's dual apprenticeship system from its organization in the 1970s; (4) apprenticeship in the dual system; (3) Germany's…

  9. Dual use display systems for telerobotics

    NASA Technical Reports Server (NTRS)

    Massimino, Michael J.; Meschler, Michael F.; Rodriguez, Alberto A.

    1994-01-01

    This paper describes a telerobotics display system, the Multi-mode Manipulator Display System (MMDS), that has applications for a variety of remotely controlled tasks. Designed primarily to assist astronauts with the control of space robotics systems, the MMDS has applications for ground control of space robotics as well as for toxic waste cleanup, undersea, remotely operated vehicles, and other environments which require remote operations. The MMDS has three modes: (1) Manipulator Position Display (MPD) mode, (2) Joint Angle Display (JAD) mode, and (3) Sensory Substitution (SS) mode. These three modes are discussed in the paper.

  10. Plasma-sprayed dual density ceramic turbine seal system

    NASA Technical Reports Server (NTRS)

    Clingman, D. L.; Schechter, B.; Cross, K. R.; Cavanagh, J. R.

    1979-01-01

    Dual density, plasma sprayed ceramic coating systems were investigated for possible application as abradable turbine tip seal systems in small gas turbine engines. Abradability, erosion resistance, internal leakage, and microstructural characterization were investigated for polyester and cenosphere filled zirconium oxide composites. Results indicate the polyester system is more abradable but displays significantly less erosion resistance than the cenosphere system. It is also stated that the absence of significant blade tip damage during abradability testing of both systems suggests additional effort may result in a more nearly optimum balance of abradability and erosion resistance.

  11. Refrigeration system having dual suction port compressor

    DOEpatents

    Wu, Guolian

    2016-01-05

    A cooling system for appliances, air conditioners, and other spaces includes a compressor, and a condenser that receives refrigerant from the compressor. The system also includes an evaporator that receives refrigerant from the condenser. Refrigerant received from the condenser flows through an upstream portion of the evaporator. A first portion of the refrigerant flows to the compressor without passing through a downstream portion of the evaporator, and a second portion of the refrigerant from the upstream portion of the condenser flows through the downstream portion of the evaporator after passing through the upstream portion of the evaporator. The second portion of the refrigerant flows to the compressor after passing through the downstream portion of the evaporator. The refrigeration system may be configured to cool an appliance such as a refrigerator and/or freezer, or it may be utilized in air conditioners for buildings, motor vehicles, or other such spaces.

  12. Stochastic image reconstruction for a dual-particle imaging system

    NASA Astrophysics Data System (ADS)

    Hamel, M. C.; Polack, J. K.; Poitrasson-Rivière, A.; Flaska, M.; Clarke, S. D.; Pozzi, S. A.; Tomanin, A.; Peerani, P.

    2016-02-01

    Stochastic image reconstruction has been applied to a dual-particle imaging system being designed for nuclear safeguards applications. The dual-particle imager (DPI) is a combined Compton-scatter and neutron-scatter camera capable of producing separate neutron and photon images. The stochastic origin ensembles (SOE) method was investigated as an imaging method for the DPI because only a minimal estimation of system response is required to produce images with quality that is comparable to common maximum-likelihood methods. This work contains neutron and photon SOE image reconstructions for a 252Cf point source, two mixed-oxide (MOX) fuel canisters representing point sources, and the MOX fuel canisters representing a distributed source. Simulation of the DPI using MCNPX-PoliMi is validated by comparison of simulated and measured results. Because image quality is dependent on the number of counts and iterations used, the relationship between these quantities is investigated.

  13. Dual-Actuator Active Vibration-Control System

    NASA Technical Reports Server (NTRS)

    Kascak, Albert F.; Kiraly, Louis J.; Montague, Gerald T.; Palazzolo, Alan B.; Manchala, Daniel

    1994-01-01

    Dual-actuator active vibration-control (DAAVC) system is developmental system of type described in "Active Vibration Dampers for Rotating Machinery" (LEW-15427). System features sensors and actuators positioned and oriented at bearings to measure and counteract vibrations of shaft along either of two axes perpendicular to axis of rotation. Effective in damping vibrations of helicopter-engine test stand, making it safer to operate engine at speeds near and above first resonance of engine/test-stand system. Opens new opportunities for engine designers to draw more power from engine, and concept applicable to other rotating machines.

  14. Dual-range linearized transimpedance amplifier system

    DOEpatents

    Wessendorf, Kurt O.

    2010-11-02

    A transimpedance amplifier system is disclosed which simultaneously generates a low-gain output signal and a high-gain output signal from an input current signal using a single transimpedance amplifier having two different feedback loops with different amplification factors to generate two different output voltage signals. One of the feedback loops includes a resistor, and the other feedback loop includes another resistor in series with one or more diodes. The transimpedance amplifier system includes a signal linearizer to linearize one or both of the low- and high-gain output signals by scaling and adding the two output voltage signals from the transimpedance amplifier. The signal linearizer can be formed either as an analog device using one or two summing amplifiers, or alternately can be formed as a digital device using two analog-to-digital converters and a digital signal processor (e.g. a microprocessor or a computer).

  15. Dual Oculometer System for Aviation Crew Assessment

    NASA Technical Reports Server (NTRS)

    Latorella, Kara; Ellis, Kyle K.; Lynn, William A.; Frasca, Dennis; Burdette, Daniel W.; Feigh, Charles T.; Douglas, Alan L.

    2010-01-01

    Oculometers, eye trackers, are a useful tool for ascertaining the manner in which pilots deploy visual attentional resources, and for assessing the degree to which stimuli capture attention exogenously. The aim of this effort was to obtain oculometer data comfortably, unobtrusively, reliably and with good spatial resolution over a standard B757-like flight deck for both individuals in a crew. We chose to implement two remote, 5-camera Smarteye systems which were crafted for this purpose to operate harmoniously. We present here the results of validation exercises, lessons learned for improving data quality, and initial thoughts on the use of paired oculometer data to reflect crew workload, coordination, and situation awareness, in the aggregate.

  16. Dual energy CT with photon counting and dual source systems: comparative evaluation.

    PubMed

    Atak, Haluk; Shikhaliev, Polad M

    2015-12-01

    Recently, new dual energy (DE) computed tomography (CT) systems-dual source CT (DSCT) and photon counting CT (PCCT) have been introduced. Although these systems have the same clinical targets, they have major differences as they use dual and single kVp acquisitions and different x-ray detection and energy resolution concepts. The purpose of this study was theoretical and experimental comparisons of DSCT and PCCT. The DSCT Siemens Somatom Flash was modeled for simulation study. The PCCT had the same configuration as DSCT except it used a photon counting detector. The soft tissue phantoms with 20, 30, and 38 cm diameters included iodine, CaCO3, adipose, and water samples. The dose (air kerma) was 14 mGy for all studies. The low and high energy CT data were simulated at 80 kVp and 140 kVp for DSCT, and in 20-58 keV and 59-120 keV energy ranges for PCCT, respectively. The experiments used Somatom Flash DSCT system and PCCT system based on photon counting CdZnTe detector with 2  ×  256 pixel configuration and 1  ×  1 mm(2) pixels size. In simulated general CT images, PCCT provided higher contrast-to-noise ratio (CNR) than DSCT with 0.4/0.8 mm Sn filters. The PCCT with K-edge filter provided higher CNR than the PCCT with a Cu filter, and DSCT with 0.4 mm Sn filter provided higher CNR than the DSCT with a 0.8 mm Sn filter. In simulated DE subtracted images, CNR of the DSCT was comparable to the PCCT with a Cu filter. However, DE PCCT with Ho a K-edge filter provided 30-40% higher CNR than the DE DSCT with 0.4/0.8 mm Sn filters. The experimental PCCT provided higher CNR in general imaging compared to the DSCT. In experimental DE subtracted images, the DSCT provided higher CNR than the PCCT with a Cu filter. However, experimental CNR with DE PCCT with K-edge filter was 15% higher than in DE DSCT, which is less than 30-40% increase predicted by the simulation study. It is concluded that ideal PCCT can provide substantial advantages over ideal

  17. Dual energy CT with photon counting and dual source systems: comparative evaluation.

    PubMed

    Atak, Haluk; Shikhaliev, Polad M

    2015-12-01

    Recently, new dual energy (DE) computed tomography (CT) systems-dual source CT (DSCT) and photon counting CT (PCCT) have been introduced. Although these systems have the same clinical targets, they have major differences as they use dual and single kVp acquisitions and different x-ray detection and energy resolution concepts. The purpose of this study was theoretical and experimental comparisons of DSCT and PCCT. The DSCT Siemens Somatom Flash was modeled for simulation study. The PCCT had the same configuration as DSCT except it used a photon counting detector. The soft tissue phantoms with 20, 30, and 38 cm diameters included iodine, CaCO3, adipose, and water samples. The dose (air kerma) was 14 mGy for all studies. The low and high energy CT data were simulated at 80 kVp and 140 kVp for DSCT, and in 20-58 keV and 59-120 keV energy ranges for PCCT, respectively. The experiments used Somatom Flash DSCT system and PCCT system based on photon counting CdZnTe detector with 2  ×  256 pixel configuration and 1  ×  1 mm(2) pixels size. In simulated general CT images, PCCT provided higher contrast-to-noise ratio (CNR) than DSCT with 0.4/0.8 mm Sn filters. The PCCT with K-edge filter provided higher CNR than the PCCT with a Cu filter, and DSCT with 0.4 mm Sn filter provided higher CNR than the DSCT with a 0.8 mm Sn filter. In simulated DE subtracted images, CNR of the DSCT was comparable to the PCCT with a Cu filter. However, DE PCCT with Ho a K-edge filter provided 30-40% higher CNR than the DE DSCT with 0.4/0.8 mm Sn filters. The experimental PCCT provided higher CNR in general imaging compared to the DSCT. In experimental DE subtracted images, the DSCT provided higher CNR than the PCCT with a Cu filter. However, experimental CNR with DE PCCT with K-edge filter was 15% higher than in DE DSCT, which is less than 30-40% increase predicted by the simulation study. It is concluded that ideal PCCT can provide substantial advantages over ideal

  18. Dual energy CT with photon counting and dual source systems: comparative evaluation

    NASA Astrophysics Data System (ADS)

    Atak, Haluk; Shikhaliev, Polad M.

    2015-12-01

    Recently, new dual energy (DE) computed tomography (CT) systems—dual source CT (DSCT) and photon counting CT (PCCT) have been introduced. Although these systems have the same clinical targets, they have major differences as they use dual and single kVp acquisitions and different x-ray detection and energy resolution concepts. The purpose of this study was theoretical and experimental comparisons of DSCT and PCCT. The DSCT Siemens Somatom Flash was modeled for simulation study. The PCCT had the same configuration as DSCT except it used a photon counting detector. The soft tissue phantoms with 20, 30, and 38 cm diameters included iodine, CaCO3, adipose, and water samples. The dose (air kerma) was 14 mGy for all studies. The low and high energy CT data were simulated at 80 kVp and 140 kVp for DSCT, and in 20-58 keV and 59-120 keV energy ranges for PCCT, respectively. The experiments used Somatom Flash DSCT system and PCCT system based on photon counting CdZnTe detector with 2  ×  256 pixel configuration and 1  ×  1 mm2 pixels size. In simulated general CT images, PCCT provided higher contrast-to-noise ratio (CNR) than DSCT with 0.4/0.8 mm Sn filters. The PCCT with K-edge filter provided higher CNR than the PCCT with a Cu filter, and DSCT with 0.4 mm Sn filter provided higher CNR than the DSCT with a 0.8 mm Sn filter. In simulated DE subtracted images, CNR of the DSCT was comparable to the PCCT with a Cu filter. However, DE PCCT with Ho a K-edge filter provided 30-40% higher CNR than the DE DSCT with 0.4/0.8 mm Sn filters. The experimental PCCT provided higher CNR in general imaging compared to the DSCT. In experimental DE subtracted images, the DSCT provided higher CNR than the PCCT with a Cu filter. However, experimental CNR with DE PCCT with K-edge filter was 15% higher than in DE DSCT, which is less than 30-40% increase predicted by the simulation study. It is concluded that ideal PCCT can provide substantial advantages over ideal

  19. The tri-Hamiltonian dual system of supersymmetric two boson system

    NASA Astrophysics Data System (ADS)

    Zhang, Mengxia; Tian, Kai; Zhang, Lei

    2016-09-01

    The dual system of the supersymmetric two boson system is constructed through the approach of tri-Hamiltonian duality, and inferred from this duality, its zero-curvature representation is also figured out. Furthermore, the dual system is shown to be equivalent to a N = 2 supersymmetric Camassa-Holm equation, and this relation results in a new linear spectral problem for the N = 2 supersymmetric Camassa-Holm equation.

  20. The role of the histaminergic system in the central cardiovascular regulation in haemorrhagic hypotension.

    PubMed

    Jochem, Jerzy; Kasperska-Zajac, Alicja

    2012-01-01

    The histaminergic system consists of neurons located in tuberomammillary nucleus of the posterior hypothalamus. It affects many functions of the central nervous system, including regulation of the brainstem cardiovascular center. In this paper, we present current review of the literature concerning the role of the histaminergic system in the cardiovascular regulation in haemorrhagic hypotension. Experimental studies demonstrate that in both, normotension and critical hemorrhagic hypotension, histamine, acting as a central neurotransmitter, evokes the pressor effect. Interestingly, increases in mean arterial pressure are significantly higher in hypovolaemic than in normovolaemic animals. Many lines of evidence support the hypothesis that in haemorrhagic shock, the histaminergic system is able to activate neural and humoral compensatory mechanisms involving the sympathetic nervous and renin-angiotensin systems, arginine vasopressin and proopiomelanocortin-derived peptides. We suggest that the histaminergic system could be a new target for treatment of hemorrhagic hypotension.

  1. A laboratory breadboard system for dual-arm teleoperation

    NASA Technical Reports Server (NTRS)

    Bejczy, A. K.; Szakaly, Z.; Kim, W. S.

    1990-01-01

    The computing architecture of a novel dual-arm teleoperation system is described. The novelty of this system is that: (1) the master arm is not a replica of the slave arm; it is unspecific to any manipulator and can be used for the control of various robot arms with software modifications; and (2) the force feedback to the general purpose master arm is derived from force-torque sensor data originating from the slave hand. The computing architecture of this breadboard system is a fully synchronized pipeline with unique methods for data handling, communication and mathematical transformations. The computing system is modular, thus inherently extendable. The local control loops at both sites operate at 100 Hz rate, and the end-to-end bilateral (force-reflecting) control loop operates at 200 Hz rate, each loop without interpolation. This provides high-fidelity control. This end-to-end system elevates teleoperation to a new level of capabilities via the use of sensors, microprocessors, novel electronics, and real-time graphics displays. A description is given of a graphic simulation system connected to the dual-arm teleoperation breadboard system. High-fidelity graphic simulation of a telerobot (called Phantom Robot) is used for preview and predictive displays for planning and for real-time control under several seconds communication time delay conditions. High fidelity graphic simulation is obtained by using appropriate calibration techniques.

  2. The sympathetic nervous system and baroreflexes in hypertension and hypotension.

    PubMed

    Izzo, J L; Taylor, A A

    1999-06-01

    Blood pressure and blood volume are closely regulated by the interrelated actions of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS). Reflex vasoconstriction caused by parallel SNS and RAAS activation is modulated by two interactive negative feedback systems called baroreflex. The aortic-carotid baroreflex systems respond to momentary changes in systolic blood pressure, adjusting the degree of SNS-dependent peripheral vasoconstriction and cardiac output to allow maintenance of a relatively constant perfusion pressure. Cardiopulmonary baroreflexes respond to momentary changes in cardiac filling, adjusting the degree of peripheral venoconstriction and venous return to maintain cardiac preload and stroke volume. Under normal conditions, each baroreflex system exhibits a degree of tonic negative feedback so that it can alter SNS output immediately, providing counterregulatory increases or decreases in pressure or volume to maintain homeostasis. The SNS is inappropriately active in obesity and hypertension and plays a causal or permissive role in all forms of chronic hypertension. If the negative feedback control exerted by the baroreflexes over the SNS and renin-angiotensin-aldosterone system (RAAS) were perfect, chronic hypertension would not occur. Activity of the baroreflexes, however, is chronically altered by maladaptive changes such as cardiac and vascular fibrosis and hypertrophy. Long-term increases in SNS and RAAS activity also exert ongoing deleterious effects on the heart and vasculature by directly facilitating further cardiac hypertrophy and arterial stiffening. These effects appear to contribute to a vicious cycle of chronic hypertension and target organ damage. Other syndromes of abnormal blood pressure (BP) control, including orthostatic hypotension and baroreflex failure are examples of abnormal baroreflex activity and SNS control. PMID:10981075

  3. The selective equipment removal system dual arm work module

    SciTech Connect

    Noakes, M.W.; Haley, D.C.; Willis, W.D.

    1997-12-31

    The Selective Equipment Removal System (SERS) was previously developed under the Department of Energy`s Robotics Technology Development Program to demonstrate and evaluate mobile telerobotic concepts for performing selective dismantlement using the reconfigurable dual-arm work module (DAWM). DAWM was designed for overhead transporter, crane hook, and mobile vehicle deployment. The DAWM configuration provided two 6-degree-of-freedom (D.O.F.) hydraulic manipulators with a maximum capacity of 240 lbs in the elbows-up configuration and five additional D.O.F. supplying torso rotate for the entire positioning package, linear extension of each arm base, and base rotate for each arm (which added a seventh D.O.F. to the manipulator for elbows-up, elbows-out, and elbows-down operation). Hydraulic manipulators were selected to provide the payload capacity required for anticipated tooling and material handling needs that would be typical of heavy dismantlement tasks. The original design of the dual arm manipulation system was driven by the desire to provide maximum system versatility in the study of deployment options and orientation relative to specific task performance. In FY 1996, the program was directed to provide remote systems support for the dismantlement of the CP5 reactor at Argonne National Lab (ANL) beginning in FY 1997. A study of the tasks involved and the available deployment options led to a rework of the DAWM designated the dual arm work platform (DAWP), which was specifically designed around crane hook deployment, reduced the base D.O.F.`s to four instead of five, and made use of the existing DAWM control system. This paper describes the evolution of the DAWM into the DAWP and the design philosophy involved.

  4. Long wavelength infrared dual field-of-view optical system

    NASA Astrophysics Data System (ADS)

    Xiong, Tao; Yang, Chang-cheng

    2007-12-01

    For cooled 320×240 staring focal plane array (FPA), a novel long wavelength infrared dual field-of-view optical system is presented in the paper. The optical system is composed of re-imaging part and zooming part. The parameters of the system are 1.96 f/number, 100% cold shield efficiency, 180mm/60mm effective focal length (EFL) and 8-10 μm spectrum region. The optical system is analyzed from two modes of narrow field of view (NFOV) and wide field of view (WFOV). The system can be used in the temperature range from-30°Cand 60°C without significant degradation of optical performance. The final test results prove the designed performance is good..

  5. Dual synchronization of fractional-order chaotic systems via a linear controller.

    PubMed

    Xiao, Jian; Ma, Zhen-zhen; Yang, Ye-Hong

    2013-01-01

    The problem of the dual synchronization of two different fractional-order chaotic systems is studied. By a linear controller, we realize the dual synchronization of fractional-order chaotic systems. Finally, the proposed method is applied for dual synchronization of Van der Pol-Willis systems and Van der Pol-Duffing systems. The numerical simulation shows the accuracy of the theory. PMID:24163612

  6. Dual Synchronization of Fractional-Order Chaotic Systems via a Linear Controller

    PubMed Central

    Xiao, Jian; Ma, Zhen-zhen; Yang, Ye-hong

    2013-01-01

    The problem of the dual synchronization of two different fractional-order chaotic systems is studied. By a linear controller, we realize the dual synchronization of fractional-order chaotic systems. Finally, the proposed method is applied for dual synchronization of Van der Pol-Willis systems and Van der Pol-Duffing systems. The numerical simulation shows the accuracy of the theory. PMID:24163612

  7. Dual-circuit, multiple-effect refrigeration system and method

    DOEpatents

    DeVault, Robert C.

    1995-01-01

    A dual circuit absorption refrigeration system comprising a high temperature single-effect refrigeration loop and a lower temperature double-effect refrigeration loop separate from one another and provided with a double-condenser coupling therebetween. The high temperature condenser of the single-effect refrigeration loop is double coupled to both of the generators in the double-effect refrigeration loop to improve internal heat recovery and a heat and mass transfer additive such as 2-ethyl-1-hexanol is used in the lower temperature double-effect refrigeration loop to improve the performance of the absorber in the double-effect refrigeration loop.

  8. Dual or unitary system? Two alternative models of decision making.

    PubMed

    Rustichini, Aldo

    2008-12-01

    In recent years, a lively debate in neuroeconomics has focused on what appears to be a fundamental question: Is the brain a unitary or a dual system? We are still far from a consensus view. The accumulating evidence supports both sides of the debate. A reason for the difficulty in reaching a convincing solution is that we do not yet have a clear theoretical model for either position. Here I review the basic elements and potential building blocks for such theories, using sources in large measure from classical decision theory and game theory.

  9. A dual chamber Gregorian subreflector system for compact range applications

    NASA Astrophysics Data System (ADS)

    Pistorius, Carl W. I.; Clerici, Giancarlo C.; Burnside, Walter D.

    1989-03-01

    A dual-chamber compact range configuration is proposed wherein the main reflector and target zone are located in the main chamber and an oversized Gregorian subreflector and associated feed assemblies in the other. The chambers are isolated by an absorber fence except for a small coupling aperture which is used to transmit signals between them. The absorber fence prevents diffraction by the subreflector and spillover by the feed from illuminating the main reflector and target zone. System performance is analyzed with and without the absorber fence to show how the coupling aperture should be shaped to minimize diffractions.

  10. A dual chamber Gregorian subreflector system for compact range applications

    NASA Technical Reports Server (NTRS)

    Pistorius, Carl W. I.; Clerici, Giancarlo C.; Burnside, Walter D.

    1989-01-01

    A dual-chamber compact range configuration is proposed wherein the main reflector and target zone are located in the main chamber and an oversized Gregorian subreflector and associated feed assemblies in the other. The chambers are isolated by an absorber fence except for a small coupling aperture which is used to transmit signals between them. The absorber fence prevents diffraction by the subreflector and spillover by the feed from illuminating the main reflector and target zone. System performance is analyzed with and without the absorber fence to show how the coupling aperture should be shaped to minimize diffractions.

  11. Dual Heat Pulse, Dual Layer Thermal Protection System Sizing Analysis and Trade Studies for Human Mars Entry Descent and Landing

    NASA Technical Reports Server (NTRS)

    McGuire, Mary Kathleen

    2011-01-01

    NASA has been recently updating design reference missions for the human exploration of Mars and evaluating the technology investments required to do so. The first of these started in January 2007 and developed the Mars Design Reference Architecture 5.0 (DRA5). As part of DRA5, Thermal Protection System (TPS) sizing analysis was performed on a mid L/D rigid aeroshell undergoing a dual heat pulse (aerocapture and atmospheric entry) trajectory. The DRA5 TPS subteam determined that using traditional monolithic ablator systems would be mass expensive. They proposed a new dual-layer TPS concept utilizing an ablator atop a low thermal conductivity insulative substrate to address the issue. Using existing thermal response models for an ablator and insulative tile, preliminary hand analysis of the dual layer concept at a few key heating points indicated that the concept showed potential to reduce TPS masses and warranted further study. In FY09, the followon Entry, Descent and Landing Systems Analysis (EDL-SA) project continued by focusing on Exploration-class cargo or crewed missions requiring 10 to 50 metric tons of landed payload. The TPS subteam advanced the preliminary dual-layer TPS analysis by developing a new process and updated TPS sizing code to rapidly evaluate mass-optimized, full body sizing for a dual layer TPS that is capable of dual heat pulse performance. This paper describes the process and presents the results of the EDL-SA FY09 dual-layer TPS analyses on the rigid mid L/D aeroshell. Additionally, several trade studies were conducted with the sizing code to evaluate the impact of various design factors, assumptions and margins.

  12. Critical insights into the beneficial and protective actions of the kallikrein-kinin system.

    PubMed

    Regoli, Domenico; Gobeil, Fernand

    2015-01-01

    Hypertension is characterized by an imbalance between the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II AT-1 receptor antagonists (also known as sartans or ARBs) are potent modulators of these systems and are highly effective as first-line treatments for hypertension, diabetic nephropathies, and diseases of the brain and coronary arteries. However, these agents are mechanistically distinct and should not be considered interchangeable. In this mini-review, we provide novel insights into the often neglected roles of the KKS in the beneficial, protective, and reparative actions of ACEIs. Indeed, ACEIs are the only antihypertensive drugs that properly reduce the imbalance between the RAS and the KKS, thereby restoring optimal cardiovascular homeostasis and significantly reducing morbidity and the risk of all-cause mortality among individuals affected by hypertension and other cardiovascular diseases. PMID:25579779

  13. Central nervous system circuits modified in heart failure: pathophysiology and therapeutic implications.

    PubMed

    Sousa-Pinto, Bernardo; Ferreira-Pinto, Manuel J; Santos, Mário; Leite-Moreira, Adelino F

    2014-11-01

    The pathophysiology of heart failure (HF) is characterized by an abnormal activation of neurohumoral systems, including the sympathetic nervous and the renin-angiotensin-aldosterone systems, which have long-term deleterious effects on the disease progression. Perpetuation of this neurohumoral activation is partially dependent of central nervous system (CNS) pathways, mainly involving the paraventricular nucleus of the hypothalamus and some regions of the brainstem. Modifications in these integrative CNS circuits result in the attenuation of sympathoinhibitory and exacerbation of sympathoexcitatory pathways. In addition to the regulation of sympathetic outflow, these central pathways coordinate a complex network of agents with an established pathophysiological relevance in HF such as angiotensin, aldosterone, and proinflammatory cytokines. Central pathways could be potential targets in HF therapy since the current mainstay of HF pharmacotherapy aims primarily at antagonizing the peripheral mechanisms. Thus, in the present review, we describe the role of CNS pathways in HF pathophysiology and as potential novel therapeutic targets.

  14. Distribution of Urocortins and Corticotropin-Releasing Factor Receptors in the Cardiovascular System

    PubMed Central

    Takahashi, Kazuhiro

    2012-01-01

    Urocortins are human homologues of urotensin I, a fish corticotropin-releasing-factor- (CRF-) like peptide secreted from the urophysis. There are three urocortins: urocortin 1, urocortin 2, and urocortin 3 in mammals. We have shown that urocortin 1 and urocortin 3 are endogenously synthesized in the myocardial cells of human heart and may act on CRF type 2 receptor (CRFR2) expressed in the heart. Expression levels of urocortin 1 in the heart and plasma urocortin 1 levels are elevated in patients with heart failure. Recent studies have shown that urocortins have various biological actions in the cardiovascular system, such as a vasodilator action, a positive inotropic action, a cardioprotective action against ischemia/reperfusion injury, and suppressive actions against the renin angiotensin system and the sympathetic nervous system. Urocortins and CRFR2 may therefore be a potential therapeutic target for cardiovascular diseases, such as congestive heart failure, hypertension, and myocardial infarction. PMID:22675352

  15. Dual-phase evolution in complex adaptive systems

    PubMed Central

    Paperin, Greg; Green, David G.; Sadedin, Suzanne

    2011-01-01

    Understanding the origins of complexity is a key challenge in many sciences. Although networks are known to underlie most systems, showing how they contribute to well-known phenomena remains an issue. Here, we show that recurrent phase transitions in network connectivity underlie emergent phenomena in many systems. We identify properties that are typical of systems in different connectivity phases, as well as characteristics commonly associated with the phase transitions. We synthesize these common features into a common framework, which we term dual-phase evolution (DPE). Using this framework, we review the literature from several disciplines to show that recurrent connectivity phase transitions underlie the complex properties of many biological, physical and human systems. We argue that the DPE framework helps to explain many complex phenomena, including perpetual novelty, modularity, scale-free networks and criticality. Our review concludes with a discussion of the way DPE relates to other frameworks, in particular, self-organized criticality and the adaptive cycle. PMID:21247947

  16. Dual-Frequency Airborne Scanning Rain Radar Antenna System

    NASA Technical Reports Server (NTRS)

    Hussein, Ziad A.; Green, Ken

    2004-01-01

    A compact, dual-frequency, dual-polarization, wide-angle-scanning antenna system has been developed as part of an airborne instrument for measuring rainfall. This system is an upgraded version of a prior single-frequency airborne rain radar antenna system and was designed to satisfy stringent requirements. One particularly stringent combination of requirements is to generate two dual-polarization (horizontal and vertical polarizations) beams at both frequencies (13.405 and 35.605 GHz) in such a way that the beams radiated from the antenna point in the same direction, have 3-dB angular widths that match within 25 percent, and have low sidelobe levels over a wide scan angle at each polarization-and-frequency combination. In addition, the system is required to exhibit low voltage standing-wave ratios at both frequencies. The system (see figure) includes a flat elliptical scanning reflector and a stationary offset paraboloidal reflector illuminated by a common-aperture feed system that comprises a corrugated horn with four input ports one port for each of the four frequency-and-polarization combinations. The feed horn is designed to simultaneously (1) under-illuminate the reflectors 35.605 GHz and (2) illuminate the reflectors with a 15-dB edge taper at 13.405 GHz. The scanning mirror is rotated in azimuth to scan the antenna beam over an angular range of 20 in the cross-track direction for wide swath coverage, and in elevation to compensate for the motion of the aircraft. The design of common-aperture feed horn makes it possible to obtain the required absolute gain and low side-lobe levels in wide-angle beam scanning. The combination of the common-aperture feed horn with the small (0.3) focal-length-to-diameter ratio of the paraboloidal reflector makes it possible for the overall system to be compact enough that it can be mounted on a DC-8 airplane.

  17. [Kallikrein-kinin system as a target for diabetic retinopathy treatment].

    PubMed

    Iarovaia, G A; Neshkova, E A; Blokhina, T B; Kochergin, S A; Vorob'eva, I V; Gigineishvili, D N

    2012-01-01

    Multifactor etiology of diabetic retinopathy (DR) determines difficulty of understanding of pathogenesis and need of search of effective approaches to study key mechanisms of development of this microvascular complication of diabetes mellitus (DM). Significant achievements of the last years show the contribution of two proteolytic systems into pathogenesis of DR, that control vascular tone and permeability - kallikrein-kinin (KKS) and renin-angiotensin systems (RAS). Among new approaches to DR treatment one of the most appropriate is an influence on KKS by means of inhibiting kallikrein, that leads to reduction of retinal vascular permeability and allows to prevent the development of macula oedema and other consequences of vascular wall damage in DR. PMID:22994115

  18. Rho kinase polymorphism influences blood pressure and systemic vascular resistance in human twins: role of heredity.

    PubMed

    Seasholtz, Tammy M; Wessel, Jennifer; Rao, Fangwen; Rana, Brinda K; Khandrika, Srikrishna; Kennedy, Brian P; Lillie, Elizabeth O; Ziegler, Michael G; Smith, Douglas W; Schork, Nicholas J; Brown, Joan Heller; O'Connor, Daniel T

    2006-05-01

    The Rho/Rho kinase (ROCK) pathway is implicated in experimental hypertension. We, therefore, explored the role of ROCK2 genetic variation in human blood pressure (BP) regulation, exploiting the advantages of a human twin sample to probe heritability. The focus of this work is the common nonsynonymous variant at ROCK2: Thr431Asn. Cardiovascular and autonomic traits displayed substantial heritability (from approximately 33% to 71%; P<0.05). The Asn/Asn genotype (compared with Asn/Thr or Thr/Thr) was associated with greater resting systolic (P<0.001), diastolic (P<0.0001), and mean BP (P<0.0001); allelic variation at ROCK2 accounted for up to approximately 5% of BP variation (P<0.0001). Systemic vascular resistance was higher in Asn/Asn individuals (P=0.049), whereas cardiac output, large artery compliance, and vasoactive hormone secretion were not different. Coupling of the renin-angiotensin system to systemic resistance and BP was diminished in Asn/Asn homozygotes, suggesting genetic pleiotropy of Thr431Asn, confirmed by bivariate genetic analyses. The Asn/Asn genotype also predicted higher BP after environmental (cold) stress. The rise in heart rate after cold was less pronounced in Asn/Asn individuals, consistent with intact baroreceptor function, and baroreceptor slope was not influenced by genotype. Common genetic variation (Thr431Asn) at ROCK2 predicts increased BP, systemic vascular resistance (although not large artery compliance), and resistance in response to the endogenous renin-angiotensin system, indicating a resistance vessel-based effect on elevated BP. The results suggest that common variation in ROCK2 exerts systemic resistance-mediated changes in BP, documenting a novel mechanism for human circulatory control, and suggesting new possibilities for diagnostic profiling and treatment of subjects at risk of developing hypertension.

  19. Dual annular rotating "windowed" nuclear reflector reactor control system

    DOEpatents

    Jacox, Michael G.; Drexler, Robert L.; Hunt, Robert N. M.; Lake, James A.

    1994-01-01

    A nuclear reactor control system is provided in a nuclear reactor having a core operating in the fast neutron energy spectrum where criticality control is achieved by neutron leakage. The control system includes dual annular, rotatable reflector rings. There are two reflector rings: an inner reflector ring and an outer reflector ring. The reflectors are concentrically assembled, surround the reactor core, and each reflector ring includes a plurality of openings. The openings in each ring are capable of being aligned or non-aligned with each other. Independent driving means for each of the annular reflector rings is provided so that reactor criticality can be initiated and controlled by rotation of either reflector ring such that the extent of alignment of the openings in each ring controls the reflection of neutrons from the core.

  20. Dual-imaging system for burn depth diagnosis.

    PubMed

    Ganapathy, Priya; Tamminedi, Tejaswi; Qin, Yi; Nanney, Lillian; Cardwell, Nancy; Pollins, Alonda; Sexton, Kevin; Yadegar, Jacob

    2014-02-01

    Currently, determination of burn depth and healing outcomes has been limited to subjective assessment or a single modality, e.g., laser Doppler imaging. Such measures have proven less than ideal. Recent developments in other non-contact technologies such as optical coherence tomography (OCT) and pulse speckle imaging (PSI) offer the promise that an intelligent fusion of information across these modalities can improve visualization of burn regions thereby increasing the sensitivity of the diagnosis. In this work, we combined OCT and PSI images to classify the degree of burn (superficial, partial-thickness and full-thickness burns). Algorithms were developed to integrate and visualize skin structure (with and without burns) from the two modalities. We have completed the proposed initiatives by employing a porcine burn model and compiled results that attest to the utility of our proposed dual-modal fusion approach. Computer-derived data indicating the varying burn depths were validated through immunohistochemical analysis performed on burned skin tissue. The combined performance of OCT and PSI modalities provided an overall ROC-AUC=0.87 (significant at p<0.001) in classifying different burn types measured after 1-h of creating the burn wounds. Porcine model studies to assess feasibility of this dual-imaging system for wound tracking are underway.

  1. The Dual System of Vocational Training in Germany. BASIS-INFO 11-1995. Social Policy.

    ERIC Educational Resources Information Center

    Kraemer, Dagmar

    The dual system of vocational training is a joint government-industry program and part of the general educational system in Germany. It provides hands-on training in private businesses coupled with specialized instruction in public vocational schools at no cost to students. The objective of the dual system is to provide young people with the best…

  2. Dual centrifuge system with flocculation improves barite recovery

    SciTech Connect

    Neidhardt, D.

    1993-03-15

    A mud-treatment system using two centrifuges and chemical flocculation to recover barite can return almost clean brine to the mud system and maintain low-gravity solids below 8.5%. The system requires no dilution to combat ultrafine particles and provides substantial cost savings on mud products, personnel, and disposal. Many conventional waste water treatment systems are useful but limited-pit volumes are reduced but not eliminated. Waste water treatment systems can help solve water supply and waste water problems for drillers. To achieve pitless, closed-loop drilling, the new method uses two centrifuges, each with dual hydraulic controls for bowl speed and scroll speed, and chemical flocculents for treatment of weighted and unweighted mud systems. This setup allows stringent control of low-gravity solids, barite recovery, and drilling waste disposal volumes. On many drilling operations, mud costs can typically be the third largest drilling cost. Thus, application of this type of barite-recovery system can provide significant cost savings and operational improvements, even if mud disposal is not a major concern.

  3. Dual Fan Separator within the Universal Waste Management System

    NASA Technical Reports Server (NTRS)

    Stapleton, Tom; Converse, Dave; Broyan, James Lee, Jr.

    2014-01-01

    Since NASA's new spacecraft in development for both LEO and Deep Space capability have considerable crew volume reduction in comparison to the Space Shuttle, it is clear that NASA requires a smaller and less expensive commode. The UTAS Universal Waste Management System (UWMS) was designed to address these new constraints, resulting in an 80% volume reduction in the cabin while enhancing performance. Whereas all of the current space commodes use air flow to capture both urine and feces and separate air from the captured air/urine mixture, the UWMS commode and urine fans and the urine separator were combined into a single unit. This unit enables use of a single motor and motor controller, which provides considerable packaging and weight efficiency. In some of the intended platform applications for the UWMS, the urine is pumped to a water reclamation system. The ISS Urine Processor Assembly (UPA) system requires delivered urine to include less than 0.25% air inclusion. Air inclusion in centrifugal urine separators is greatly dependent on its rotational speed. To satisfy this requirement, a gear reducer was included, allowing the fans to rotate at a much higher speed than the separator. This new design, the Dual Fan Separator (DFS) has been designed, prototyped and tested. This paper will outline the studies and analysis performed to develop the design configuration for testing. The studies included a configuration trade study, dynamic stability analysis of the rotating bodies and a performance analysis of included labyrinth seals. NASA is considereing a program to fly the UWMS aboard the ISS as a flight experiment. The goal of the design activity is to elevate the Technical Readiness Level (TRL) of the Dual Fan Separator and determine if the concept is ready to be included in flight experiment deliverable.

  4. Study of the enantioseparation capability of chiral dual system based on chondroitin sulfate C in CE.

    PubMed

    Chen, Jiaquan; Du, Yingxiang; Zhu, Fenxia; Chen, Bin; Zhang, Qi; Du, Shuaijing; Li, Ping

    2015-02-01

    It has been reported that chiral dual system is able to improve the enantioseparation of enantiomers in many cases. Currently, the dual systems involved in CE chiral separation are mostly dual CDs systems, and the polysaccharides-based chiral dual system was reported in only one paper. To the best of our knowledge, the use of chondroitin sulfate C (CSC)-based dual system for enantiomeric separation has not been reported previously. Herein, four CSC-based chiral dual systems, namely CSC/glycogen, CSC/chondroitin sulfate A (CSA), CSC/hydroxypropyl-β-CD (HP-β-CD), as well as CSC/β-CD (β-CD), were evaluated for the first time for their enantioseparation capability by CE in this paper. During the course of the work, the influences of chiral selector concentration and buffer pH values on enantioseparation in dual systems were systematically investigated. Under the optimized conditions, the dual system consisting of CSC and glycogen exhibited better separations toward nefopam, duloxetine, sulconazole, atenolol, laudanosine, and cetirizine enantiomers compared to the single CSC or glycogen system. The combination of CSC and HP-β-CD improved the separation of amlodipine and chlorphenamine enantiomers. However, no synergistic effect was observed in the CSC/CSA and CSC/β-CD systems.

  5. Athermalization for infrared dual field-of-view optical system

    NASA Astrophysics Data System (ADS)

    Yang, Changcheng; Li, Shenghui

    2008-03-01

    With the principle of mechanical passive athermalization, a method of making the dual field-of-view (DFOV) switching zoom system for passive athermalization is presented. The long effective focal length (EFL) and short EFL have the same focus shift values of temperature by optical material combination of switching groups. So the long EFL and short EFL of this system achieve the best temperature compensation simultaneously by moving the compensated lens with the same distance, and the system has the best images and parfocality in a large working temperature. A DFOV switching zoom system is designed. It has a relative aperture of f/4.0, 100% cold shield efficiency, the EFL of 180mm/60mm at 3.7-4.8μm. The movement of compensated lens can be achieved with four layers of aluminum/titanium materials. Compared with the MTF of a normal switching zoom system without athermalization, this system needn't move the compensated lens repeatedly to obtain the best images from -30°C to 70°C and enhances the performance of target tracking and recognition.

  6. Dual strain gage balance system for measuring light loads

    NASA Technical Reports Server (NTRS)

    Roberts, Paul W. (Inventor)

    1991-01-01

    A dual strain gage balance system for measuring normal and axial forces and pitching moment of a metric airfoil model imparted by aerodynamic loads applied to the airfoil model during wind tunnel testing includes a pair of non-metric panels being rigidly connected to and extending towards each other from opposite sides of the wind tunnel, and a pair of strain gage balances, each connected to one of the non-metric panels and to one of the opposite ends of the metric airfoil model for mounting the metric airfoil model between the pair of non-metric panels. Each strain gage balance has a first measuring section for mounting a first strain gage bridge for measuring normal force and pitching moment and a second measuring section for mounting a second strain gage bridge for measuring axial force.

  7. Dual Systems Competence [Image Omitted] Procedural Processing: A Relational Developmental Systems Approach to Reasoning

    ERIC Educational Resources Information Center

    Ricco, Robert B.; Overton, Willis F.

    2011-01-01

    Many current psychological models of reasoning minimize the role of deductive processes in human thought. In the present paper, we argue that deduction is an important part of ordinary cognition and we propose that a dual systems Competence [image omitted] Procedural processing model conceptualized within relational developmental systems theory…

  8. Method and system for dual resolution translation stage

    DOEpatents

    Halpin, John Michael

    2014-04-22

    A dual resolution translation stage includes a stage assembly operable to receive an optical element and a low resolution adjustment device mechanically coupled to the stage assembly. The dual resolution stage also includes an adjustable pivot block mechanically coupled to the stage assembly. The adjustable pivot block includes a pivot shaft. The dual resolution stage further includes a lever arm mechanically coupled to the adjustable pivot block. The lever arm is operable to pivot about the pivot shaft. The dual resolution stage additionally includes a high resolution adjustment device mechanically coupled to the lever arm and the stage assembly.

  9. Control system for cheng dual-fluid cycle engine system

    SciTech Connect

    Cheng, D.Y.

    1987-07-21

    A dual-fluid heat engine is described which is operated to produce co-generated process steam having: a chamber; compressor means for introducing a first gaseous working fluid comprising air into the chamber, the compressor means having a predetermined pressure ratio (CPR); means for introducing a second liquid-vapor working fluid comprising water in the form of a vapor within the chamber at a defined water/air working fluid ratio (XMIX); means for heating the water vapor and air in the chamber at a defined specific heat input rate (SHIR); turbine means responsive to the mixture of the first and second working fluids for converting the energy associated with the mixture to mechanical energy, the temperature of the mixture entering the turbine means defining the turbine inlet temperature (TIT) and having a design maximum turbine inlet temperature (TITmax); counterflow heat exchanger means for transferring residual thermal energy from the exhausted mixture of first and second working fluids to the incoming working fluid water to thereby preheat the same to water vapor prior to its introduction within the chamber; means for diverting water vapor from the chamber, if desired, for co-generated process steam; and wherein the improvement comprises: means for operating the engine under partial load conditions such that when substantially no co-generated process steam is required. The engine control path follows a locus of peak efficiency points resulting in declining TIT as the load decreases, and such that XMIX and SHIR are selected so that for a given value of TIT, XMIX is at or near XMIX peak, where XMIX peak occurs when conditions are met simultaneously.

  10. The German 'Dual System' of Occupational Training: A Much-Replicated but Oft-Failed Transfer.

    ERIC Educational Resources Information Center

    Wilson, David N.

    Germany's Dual System, which consists of in-school and in-enterprise components, facilitates entry into 374 recognized technical, white-collar and blue-collar occupations listed in training regulations that are grounded in legislation. The Dual System's origins and development in Germany were examined along with several attempts to replicate the…

  11. Regulatory networks and complex interactions between the insulin and angiotensin II signalling systems: models and implications for hypertension and diabetes.

    PubMed

    Cizmeci, Deniz; Arkun, Yaman

    2013-01-01

    The cross-talk between insulin and angiotensin II signalling pathways plays a significant role in the co-occurrence of diabetes and hypertension. We developed a mathematical model of the system of interactions among the biomolecules that are involved in the cross-talk between the insulin and angiotensin II signalling pathways. We have identified several feedback structures that regulate the dynamic behavior of the individual signalling pathways and their interactions. Different scenarios are simulated and dominant steady-state, dynamic and stability characteristics are revealed. The proposed mechanistic model describes how angiotensin II inhibits the actions of insulin and impairs the insulin-mediated vasodilation. The model also predicts that poor glycaemic control induced by diabetes contributes to hypertension by activating the renin angiotensin aystem.

  12. Abradable dual-density ceramic turbine seal system

    NASA Technical Reports Server (NTRS)

    Clingman, D. L.; Schechter, B.; Cross, K. R.; Cavanagh, J. R.

    1981-01-01

    A plasma sprayed dual density ceramic abradable seal system for direct application to the HPT seal shroud of small gas turbine engines. The system concept is based on the thermal barrier coating and depends upon an additional layer of modified density ceramic material adjacent to the gas flow path to provide the desired abradability. This is achieved by codeposition of inert fillers with yttria stabilized zirconia (YSZ) to interrupt the continuity of the zirconia struture. The investigation of a variety of candidate fillers, with hardness values as low as 2 on Moh's scale, led to the conclusion that solid filler materials in combination with a YSZ matrix, regardless of their hardness values, have a propensity for compacting rather than shearing as originally expected. The observed compaction is accompanied by high energy dissipation in the rub interaction, usually resulting in the adhesive transfer of blade material to the stationary seal member. Two YSZ based coating systems which incorported hollow alumino silicate spheres as density reducing agents were surveyed over the entire range of compositions from 100 percent filler to 100 percent YSZ. Abradability and erosion characteristics were determined, hardness and permeability characterized, and engine experience acquired with several system configurations.

  13. General equilibrium characteristics of a dual-lift helicopter system

    NASA Technical Reports Server (NTRS)

    Cicolani, L. S.; Kanning, G.

    1986-01-01

    The equilibrium characteristics of a dual-lift helicopter system are examined. The system consists of the cargo attached by cables to the endpoints of a spreader bar which is suspended by cables below two helicopters. Results are given for the orientation angles of the suspension system and its internal forces, and for the helicopter thrust vector requirements under general circumstances, including nonidentical helicopters, any accelerating or static equilibrium reference flight condition, any system heading relative to the flight direction, and any distribution of the load to the two helicopters. Optimum tether angles which minimize the sum of the required thrust magnitudes are also determined. The analysis does not consider the attitude degrees of freedom of the load and helicopters in detail, but assumes that these bodies are stable, and that their aerodynamic forces in equilibrium flight can be determined independently as functions of the reference trajectory. The ranges of these forces for sample helicopters and loads are examined and their effects on the equilibrium characteristics are given parametrically in the results.

  14. In-Flight performance of MESSENGER's Mercury dual imaging system

    USGS Publications Warehouse

    Hawkins, S.E.; Murchie, S.L.; Becker, K.J.; Selby, C.M.; Turner, F.S.; Noble, M.W.; Chabot, N.L.; Choo, T.H.; Darlington, E.H.; Denevi, B.W.; Domingue, D.L.; Ernst, C.M.; Holsclaw, G.M.; Laslo, N.R.; Mcclintock, W.E.; Prockter, L.M.; Robinson, M.S.; Solomon, S.C.; Sterner, R.E.

    2009-01-01

    The Mercury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft, launched in August 2004 and planned for insertion into orbit around Mercury in 2011, has already completed two flybys of the innermost planet. The Mercury Dual Imaging System (MDIS) acquired nearly 2500 images from the first two flybys and viewed portions of Mercury's surface not viewed by Mariner 10 in 1974-1975. Mercury's proximity to the Sun and its slow rotation present challenges to the thermal design for a camera on an orbital mission around Mercury. In addition, strict limitations on spacecraft pointing and the highly elliptical orbit create challenges in attaining coverage at desired geometries and relatively uniform spatial resolution. The instrument designed to meet these challenges consists of dual imagers, a monochrome narrow-angle camera (NAC) with a 1.5?? field of view (FOV) and a multispectral wide-angle camera (WAC) with a 10.5?? FOV, co-aligned on a pivoting platform. The focal-plane electronics of each camera are identical and use a 1024??1024 charge-coupled device detector. The cameras are passively cooled but use diode heat pipes and phase-change-material thermal reservoirs to maintain the thermal configuration during the hot portions of the orbit. Here we present an overview of the instrument design and how the design meets its technical challenges. We also review results from the first two flybys, discuss the quality of MDIS data from the initial periods of data acquisition and how that compares with requirements, and summarize how in-flight tests are being used to improve the quality of the instrument calibration. ?? 2009 SPIE.

  15. 14 CFR 105.43 - Use of single-harness, dual-parachute systems.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Use of single-harness, dual-parachute... TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES PARACHUTE OPERATIONS Parachute Equipment and Packing § 105.43 Use of single-harness, dual-parachute systems. No person may conduct a...

  16. 14 CFR 105.43 - Use of single-harness, dual-parachute systems.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Use of single-harness, dual-parachute... TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES PARACHUTE OPERATIONS Parachute Equipment and Packing § 105.43 Use of single-harness, dual-parachute systems. No person may conduct a...

  17. 14 CFR 105.43 - Use of single-harness, dual-parachute systems.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Use of single-harness, dual-parachute... TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES PARACHUTE OPERATIONS Parachute Equipment and Packing § 105.43 Use of single-harness, dual-parachute systems. No person may conduct a...

  18. A Dual Communication and Imaging Underwater Acoustic System

    NASA Astrophysics Data System (ADS)

    Fu, Tricia C.

    A dual communication and imaging underwater acoustic system is proposed and developed throughout this dissertation. Due to the wide variation in underwater channel characteristics, the research here focuses more on robustness to multipath in the shallow underwater acoustic environment, rather than high bit-rate applications and signaling schemes. Lower bit-rate (in the hundreds of bits per second (bps) to low kbps), applications such as the transfer of ecological telemetry data, e.g. conductivity or temperature data, are the primary focus of this dissertation. The parallels between direct sequence spread spectrum in digital communication and pulse-echo with pulse compression in imaging, and channel estimation in communication and range profile estimation in imaging are drawn, leading to a unified communications and imaging platform. A digital communication algorithm for channel order and channel coefficient estimation and symbol demodulation using Matching Pursuit (MP) with Generalized Multiple Hypothesis Testing (GMHT) is implemented in programmable DSP in real time with field experiment results in varying underwater environments for the single receiver (Rx), single transmitter (Tx) case. The custom and off-the-shelf hardware used in the single receiver, single transmitter set of experiments are detailed as well. This work is then extended to the single-input multiple-output (SIMO) case, and then to the full multiple-input multiple-output (MIMO) case. The results of channel estimation are used for simple range profile imaging reconstructions. Successful simulated and experimental results for both transducer array configurations are presented and analyzed. Non-real-time symbol demodulation and channel estimation is performed using experimental data from a scaled testing environment. New hardware based on cost-effective fish-finder transducers for a 6 Rx--1 Tx and 6 Rx--4 Tx transducer array is detailed. Lastly, in an application that is neither communication nor

  19. A dual-sided coded-aperture radiation detection system

    NASA Astrophysics Data System (ADS)

    Penny, R. D.; Hood, W. E.; Polichar, R. M.; Cardone, F. H.; Chavez, L. G.; Grubbs, S. G.; Huntley, B. P.; Kuharski, R. A.; Shyffer, R. T.; Fabris, L.; Ziock, K. P.; Labov, S. E.; Nelson, K.

    2011-10-01

    We report the development of a large-area, mobile, coded-aperture radiation imaging system for localizing compact radioactive sources in three dimensions while rejecting distributed background. The 3D Stand-Off Radiation Detection System (SORDS-3D) has been tested at speeds up to 95 km/h and has detected and located sources in the millicurie range at distances of over 100 m. Radiation data are imaged to a geospatially mapped world grid with a nominal 1.25- to 2.5-m pixel pitch at distances out to 120 m on either side of the platform. Source elevation is also extracted. Imaged radiation alarms are superimposed on a side-facing video log that can be played back for direct localization of sources in buildings in urban environments. The system utilizes a 37-element array of 5×5×50 cm 3 cesium-iodide (sodium) detectors. Scintillation light is collected by a pair of photomultiplier tubes placed at either end of each detector, with the detectors achieving an energy resolution of 6.15% FWHM (662 keV) and a position resolution along their length of 5 cm FWHM. The imaging system generates a dual-sided two-dimensional image allowing users to efficiently survey a large area. Imaged radiation data and raw spectra are forwarded to the RadioNuclide Analysis Kit (RNAK), developed by our collaborators, for isotope ID. An intuitive real-time display aids users in performing searches. Detector calibration is dynamically maintained by monitoring the potassium-40 peak and digitally adjusting individual detector gains. We have recently realized improvements, both in isotope identification and in distinguishing compact sources from background, through the installation of optimal-filter reconstruction kernels.

  20. Vortex dynamics in self-dual Chern-Simons-Higgs systems

    SciTech Connect

    Kim, Y. ); Lee, K. )

    1994-02-15

    We consider vortex dynamics in self-dual Chern-Simons-Higgs systems. We show that the naive Aharonov-Bohm phase is the inverse of the statistical phase expected from the vortex spin, and that the self-dual configurations of vortices are degenerate in energy but not in angular momentum. We also use the path integral formalism to derive the dual formulation of Chern-Simons-Higgs systems in which vortices appear as charged particles. We argue that in addition to the electromagnetic interaction, there is an additional interaction between vortices, the so-called Magnus force, and that these forces can be put together into a single dual electromagnetic'' interaction. This dual electromagnetic interaction leads to the right statistical phase. We also derive and study the effective action for slowly moving vortices, which contains terms both linear and quadratic in the vortex velocity. We show that vortices can be bounded to each other by the Magnus force.

  1. 32-megapixel dual-color CCD imaging system

    NASA Astrophysics Data System (ADS)

    Stubbs, Christopher W.; Marshall, Stuart; Cook, Kenneth H.; Hills, Robert F.; Noonan, Joseph; Akerlof, Carl W.; Alcock, Charles R.; Axelrod, Timothy S.; Bennett, D.; Dagley, K.; Freeman, K. C.; Griest, Kim; Park, Hye-Sook; Perlmutter, Saul; Peterson, Bruce A.; Quinn, Peter J.; Rodgers, A. W.; Sosin, C.; Sutherland, W. J.

    1993-07-01

    We have developed an astronomical imaging system that incorporates a total of eight 2048 X 2048 pixel CCDs into two focal planes, to allow simultaneous imaging in two colors. Each focal plane comprises four 'edge-buttable' detector arrays, on custom Kovar mounts. The clocking and bias voltage levels for each CCD are independently adjustable, but all the CCDs are operated synchronously. The sixteen analog outputs (two per chip) are measured at 16 bits with commercially available correlated double sampling A/D converters. The resulting 74 MBytes of data per frame are transferred over fiber optic links into dual-ported VME memory. The total readout time is just over one minute. We obtain read noise ranging from 6.5 e- to 10 e- for the various channels when digitizing at 34 Kpixels/sec, with full well depths (MPP mode) of approximately 100,000 e- per 15 micrometers X 15 micrometers pixel. This instrument is currently being used in a search of gravitational microlensing from compact objects in our Galactic halo, using the newly refurbished 1.3 m telescope at the Mt. Stromlo Observatory, Australia.

  2. Sample Analysis Code System for the Dual Channel Counter.

    1994-09-14

    Version 00 RADCOMPT automates gross alpha and gross beta sample analysis calculations and, in many cases, warns the technologist when a hazard level is being approached or when it has been exceeded. The RADCOMPT program is unique in that it corrects for crosstalk between channels, and in this way provides increased accuracy and efficiency. Even though it is designed explicitly for the analyses of air samples and wipe samples, it can also be used formore » other sample types. It is designed to be used with a dual channel counter (in which one channel is used for alpha detection and the other for beta detection), but may be used with two single channel counters employed for the same purpose. In addition, it provides an automated means for the execution of the following radiological sample analyses protocol: A. Calibration of the counting system B. Calculation of sample activity or air activity concentrations (with the activities of air activity concentrations at the top and bottom of the two-sided 95 percent confidence interval also specified). C. Determination of minimum sample counting times required for detection and/or quantification of specified alpha and beta activities or air activity concentrations. In addition, alternate counting times are determined for alternate activities such that the specified alpha and beta activities are at the top of the 95% confidence interval, increasing the confidence that the activities measured are below the specified limits. D. Calculation of the minimum detectable activities or air activity concentrations. E. Determination of air sample volumes required for detection and/or quantification of specified alpha and beta air activity concentrations. F. Calculation of long-lived activities or air activity concentrations based on radon daughter and thoron daughter decay. G. Calculation of employees DAC-Hours and estimated Committed Effective Dose Equivalent. H. Varying calibration constants (to coincide with possible adjustments to

  3. Dual Fan Separator within the Universal Waste Management System

    NASA Technical Reports Server (NTRS)

    Stapleton, Tom; Converse, Dave; Broyan, James Lee, Jr.

    2014-01-01

    Since NASA's new spacecraft in development for both LEO and Deep Space capability have considerable crew volume reduction in comparison to the Space Shuttle, the need became apparent for a smaller commode. In response the Universal Waste Management System (UWMS) was designed, resulting in an 80% volume reduction from the last US commode, while enhancing performance. The ISS WMS and previous shuttle commodes have a fan supplying air flow to capture feces and a separator to capture urine and separate air from the captured air/urine mixture. The UWMS combined both rotating equipment components into a single unit, referred to at the Dual Fan Separator (DFS). The combination of these components resulted in considerable packaging efficiency and weight reduction, removing inter-component plumbing, individual mounting configurations and required only a single motor and motor controller, in some of the intended UWMS platform applications the urine is pumped to the ISS Urine Processor Assembly (UPA) system. It requires the DFS to include less than 2.00% air inclusion, by volume, in the delivered urine. The rotational speed needs to be kept as low as possible in centrifugal urine separators to reduce air inclusion in the pumped fluid, while fans depend on rotational speed to develop delivered head. To satisfy these conflicting requirements, a gear reducer was included, allowing the fans to rotate at a much higher speed than the separator. This paper outlines the studies and analysis performed to develop the DFS configuration. The studies included a configuration trade study, dynamic stability analysis of the rotating bodies and a performance analysis of included labyrinth seals. NASA is considering a program to fly the UWMS aboard the ISS as a flight experiment. The goal of this activity is to advance the Technical Readiness Level (TRL) of the DFS and determine if the concept is ready to be included as part of the flight experiment deliverable.

  4. Toward an Automatic Calibration of Dual Fluoroscopy Imaging Systems

    NASA Astrophysics Data System (ADS)

    Al-Durgham, Kaleel; Lichti, Derek; Kuntze, Gregor; Sharma, Gulshan; Ronsky, Janet

    2016-06-01

    High-speed dual fluoroscopy (DF) imaging provides a novel, in-vivo solution to quantify the six-degree-of-freedom skeletal kinematics of humans and animals with sub-millimetre accuracy and high temporal resolution. A rigorous geometric calibration of DF system parameters is essential to ensure precise bony rotation and translation measurements. One way to achieve the system calibration is by performing a bundle adjustment with self-calibration. A first-time bundle adjustment-based system calibration was recently achieved. The system calibration through the bundle adjustment has been shown to be robust, precise, and straightforward. Nevertheless, due to the inherent absence of colour/semantic information in DF images, a significant amount of user input is needed to prepare the image observations for the bundle adjustment. This paper introduces a semi-automated methodology to minimise the amount of user input required to process calibration images and henceforth to facilitate the calibration task. The methodology is optimized for processing images acquired over a custom-made calibration frame with radio-opaque spherical targets. Canny edge detection is used to find distinct structural components of the calibration images. Edge-linking is applied to cluster the edge pixels into unique groups. Principal components analysis is utilized to automatically detect the calibration targets from the groups and to filter out possible outliers. Ellipse fitting is utilized to achieve the spatial measurements as well as to perform quality analysis over the detected targets. Single photo resection is used together with a template matching procedure to establish the image-to-object point correspondence and to simplify target identification. The proposed methodology provided 56,254 identified-targets from 411 images that were used to run a second-time bundle adjustment-based DF system calibration. Compared to a previous fully manual procedure, the proposed methodology has

  5. Dual interferometer system for measuring index of refraction

    NASA Astrophysics Data System (ADS)

    Goodwin, Eric Peter

    The optical power of a lens is determined by the surface curvature and the refractive index, n. Knowledge of the index is required for accurate lens design models and for examining material variations from sample to sample. The refractive index of glass can be accurately measured using a prism spectrometer, but measuring the index of soft contact lens materials presents many challenges. These materials are non-rigid, thin, and must remain hydrated in a saline solution during testing. Clearly an alternative to a prism spectrometer must be used to accurately measure index. A Dual Interferometer System has been designed, built and characterized as a novel method for measuring the refractive index of transparent optical materials, including soft contact lens materials. The first interferometer is a Low Coherence Interferometer in a Twyman-Green configuration with a scanning reference mirror. The contact lens material sample is placed in a measurement cuvette, where it remains hydrated. By measuring the locations of the multiple optical interfaces, the physical thickness t of the material is measured. A new algorithm has been developed for processing the low coherence signals obtained from the reflection at each optical interface. The second interferometer is a Mach-Zehnder interferometer with a tunable HeNe laser light source. This interferometer measures the optical path length (OPL) of the test sample in the cuvette in transmission as a function of five wavelengths in the visible spectrum. This is done using phase-shifting interferometry. Multiple thickness regions are used to solve 2pi phase ambiguities in the OPL. The outputs of the two interferometers are combined to determine the refractive index as a function of wavelength: n(lambda) = OPL(lambda)/t. Since both t and OPL are measured using a detector array, n is measured at hundreds of thousands of data points. A measurement accuracy of 0.0001 in refractive index is achieved with this new instrument, which is

  6. Technology requirements for advanced earth orbital transportation systems. Volume 3: Summary report - dual mode propulsion

    NASA Technical Reports Server (NTRS)

    Hepler, A. K.; Bangsund, E. L.

    1978-01-01

    The impact of dual-mode propulsion on cost-effective technology requirements for advanced earth-orbital transportation systems is considered. Additional objectives were to determine the advantages of the best dual mode concept relative to the LO2/LH2 concept of the basic study. Normal technology requirements applicable to horizontal take-off and landing single-stage-to-orbit systems utilizing dual mode rocket propulsion were projected to the 1985 time period. These technology projections were then incorporated in a vehicle parametric design analysis for two different operational concepts of a dual mode propulsion system. The resultant performance, weights and costs of each concept were compared. The selected propulsion concept was evaluated to confirm the parametric trending/scaling of weights and to optimize the configuration.

  7. Dual-Fuel Propulsion in Single-Stage Advanced Manned Launch System Vehicle

    NASA Technical Reports Server (NTRS)

    Lepsch, Roger A., Jr.; Stanley, Douglas O.; Unal, Resit

    1995-01-01

    As part of the United States Advanced Manned Launch System study to determine a follow-on, or complement, to the Space Shuttle, a reusable single-stage-to-orbit concept utilizing dual-fuel rocket propulsion has been examined. Several dual-fuel propulsion concepts were investigated. These include: a separate-engine concept combining Russian RD-170 kerosene-fueled engines with space shuttle main engine-derivative engines: the kerosene- and hydrogen-fueled Russian RD-701 engine; and a dual-fuel, dual-expander engine. Analysis to determine vehicle weight and size characteristics was performed using conceptual-level design techniques. A response-surface methodology for multidisciplinary design was utilized to optimize the dual-fuel vehicles with respect to several important propulsion-system and vehicle design parameters, in order to achieve minimum empty weight. The tools and methods employed in the analysis process are also summarized. In comparison with a reference hydrogen- fueled single-stage vehicle, results showed that the dual-fuel vehicles were from 10 to 30% lower in empty weight for the same payload capability, with the dual-expander engine types showing the greatest potential.

  8. The Mercury Dual Imaging System on the MESSENGER Spacecraft

    NASA Astrophysics Data System (ADS)

    Hawkins, S. Edward; Boldt, John D.; Darlington, Edward H.; Espiritu, Raymond; Gold, Robert E.; Gotwols, Bruce; Grey, Matthew P.; Hash, Christopher D.; Hayes, John R.; Jaskulek, Steven E.; Kardian, Charles J.; Keller, Mary R.; Malaret, Erick R.; Murchie, Scott L.; Murphy, Patricia K.; Peacock, Keith; Prockter, Louise M.; Reiter, R. Alan; Robinson, Mark S.; Schaefer, Edward D.; Shelton, Richard G.; Sterner, Raymond E.; Taylor, Howard W.; Watters, Thomas R.; Williams, Bruce D.

    2007-08-01

    The Mercury Dual Imaging System (MDIS) on the MESSENGER spacecraft will provide critical measurements tracing Mercury’s origin and evolution. MDIS consists of a monochrome narrow-angle camera (NAC) and a multispectral wide-angle camera (WAC). The NAC is a 1.5° field-of-view (FOV) off-axis reflector, coaligned with the WAC, a four-element refractor with a 10.5° FOV and 12-color filter wheel. The focal plane electronics of each camera are identical and use a 1,024×1,024 Atmel (Thomson) TH7888A charge-coupled device detector. Only one camera operates at a time, allowing them to share a common set of control electronics. The NAC and the WAC are mounted on a pivoting platform that provides a 90° field-of-regard, extending 40° sunward and 50° anti-sunward from the spacecraft + Z-axis—the boresight direction of most of MESSENGER’s instruments. Onboard data compression provides capabilities for pixel binning, remapping of 12-bit data into 8 bits, and lossless or lossy compression. MDIS will acquire four main data sets at Mercury during three flybys and the two-Mercury-solar-day nominal mission: a monochrome global image mosaic at near-zero emission angles and moderate incidence angles, a stereo-complement map at off-nadir geometry and near-identical lighting, multicolor images at low incidence angles, and targeted high-resolution images of key surface features. These data will be used to construct a global image base map, a digital terrain model, global maps of color properties, and mosaics of high-resolution image strips. Analysis of these data will provide information on Mercury’s impact history, tectonic processes, the composition and emplacement history of volcanic materials, and the thickness distribution and compositional variations of crustal materials. This paper summarizes MDIS’s science objectives and technical design, including the common payload design of the MDIS data processing units, as well as detailed results from ground and early flight

  9. Reductions of self-dual Yang-Mills fields and classical systems

    NASA Astrophysics Data System (ADS)

    Chakravarty, S.; Ablowitz, M. J.; Clarkson, P. A.

    1990-08-01

    One-dimensional reductions of the self-dual Yang-Mills equations yield various classical systems depending on the choice of the Lie algebra associated with the self-dual fields. Included are the Euler-Arnold equations for rigid bodies in n dimensions, the Kovalevskaya top, and a generalization of the Nahm equation which is related to a classical third-order differential equation possessing a movable natural boundary in the complex plane.

  10. Research on dual spectrum solar-blind ultraviolet corona detection system

    NASA Astrophysics Data System (ADS)

    Yang, Feng; Gu, Yan; Sun, Jianning; Pan, Jingsheng; Zhu, Bo; Wang, Qi; Lu, Xiaoqing

    2015-04-01

    A dual spectrum solar-blind ultraviolet (UV) corona detection system is designed in this paper. A common optical axis using a dichroic mirror is applied to this system in order to make visible light and ultraviolet light spectroscopy to ultraviolet detector and visible detectors. A high speed circuit of image processing based on TMS320DM642 DSP and a circuit that is used into system control and power management based on microcontroller are designed for the presented system. On the basis of the multi-threaded programming ideas, real-time image acquisition of ultraviolet and visible detectors, ultraviolet image noise reduction, image registration, dual spectral integration, Characteristic superimposing, serial communication and image display are achieved by using the DSP image processing circuit. Experimental results show that the dual spectrum solar-blind ultraviolet corona detection system has a good performance of corona detection based on ultraviolet and visible image fusion.

  11. Parameter estimation for a dual-rate system with time delay.

    PubMed

    Chen, Lei; Han, Lili; Huang, Biao; Liu, Fei

    2014-09-01

    This paper investigates the parameter estimation problem of the dual-rate system with time delay. The slow-rate model of the dual-rate system with time delay is derived by using the discretization technique. The parameters and states of the system are simultaneously estimated. The states are estimated by using the Kalman filter, and the parameters are estimated based on the stochastic gradient algorithm or the recursive least squares algorithm. When concerning state estimate of the dual-rate system with time delay, the state augmentation method is employed with lower computational load than that of the conventional one. Simulation examples and an experimental study are given to illustrate the proposed algorithm.

  12. An acoustic dual filter in the audio frequencies with two local resonant systems

    NASA Astrophysics Data System (ADS)

    Liu, Zhao-qun; Zhang, Hui; Zhang, Shu-yi; Fan, Li

    2014-08-01

    We report an acoustic dual filter to realize the sound regulation in the audio frequency range, in which resonant vibrations of two membrane-air and metal-elastomer systems generate two sound transmission peaks and a sound blocking below 3000 Hz. The local vibrational profiles manifest that the transmission peak at lower frequency is mainly dependent on the resonant vibration of the membrane-air system, and the coupling vibrations of two systems generate the blocking frequency and transmission peak at higher frequency. Importantly, two transmission peaks can be controlled independently. It is feasible to realize the acoustic device in sound shield and dual filters.

  13. Compact wearable dual-mode imaging system for real-time fluorescence image-guided surgery

    NASA Astrophysics Data System (ADS)

    Zhu, Nan; Huang, Chih-Yu; Mondal, Suman; Gao, Shengkui; Huang, Chongyuan; Gruev, Viktor; Achilefu, Samuel; Liang, Rongguang

    2015-09-01

    A wearable all-plastic imaging system for real-time fluorescence image-guided surgery is presented. The compact size of the system is especially suitable for applications in the operating room. The system consists of a dual-mode imaging system, see-through goggle, autofocusing, and auto-contrast tuning modules. The paper will discuss the system design and demonstrate the system performance.

  14. Compact wearable dual-mode imaging system for real-time fluorescence image-guided surgery

    PubMed Central

    Zhu, Nan; Huang, Chih-Yu; Mondal, Suman; Gao, Shengkui; Huang, Chongyuan; Gruev, Viktor; Achilefu, Samuel; Liang, Rongguang

    2015-01-01

    Abstract. A wearable all-plastic imaging system for real-time fluorescence image-guided surgery is presented. The compact size of the system is especially suitable for applications in the operating room. The system consists of a dual-mode imaging system, see-through goggle, autofocusing, and auto-contrast tuning modules. The paper will discuss the system design and demonstrate the system performance. PMID:26358823

  15. Theoretical study of a dual harmonic system and its application to the CSNS/RCS

    NASA Astrophysics Data System (ADS)

    Yuan, Yao-Shuo; Wang, Na; Xu, Shou-Yan; Yuan, Yue; Wang, Sheng

    2015-12-01

    Dual harmonic systems have been widely used in high intensity proton synchrotrons to suppress the space charge effect, as well as reduce the beam loss. To investigate the longitudinal beam dynamics in a dual rf system, the potential well, the sub-buckets in the bunch and the multi-solutions of the phase equation are studied theoretically in this paper. Based on these theoretical studies, optimization of bunching factor and rf voltage waveform are made for the dual harmonic rf system in the upgrade phase of the China Spallation Neutron Source Rapid Cycling Synchrotron (CSNS/RCS). In the optimization process, the simulation with space charge effect is done using a newly developed code, C-SCSIM. Supported by National Natural Science Foundation of China (11175193)

  16. Comparison of Analytical Predictions and Experimental Results for a Dual Brayton Power System (Discussion on Test Hardware and Computer Model for a Dual Brayton System)

    NASA Technical Reports Server (NTRS)

    Johnson, Paul K.

    2007-01-01

    NASA Glenn Research Center (GRC) contracted Barber-Nichols, Arvada, CO to construct a dual Brayton power conversion system for use as a hardware proof of concept and to validate results from a computational code known as the Closed Cycle System Simulation (CCSS). Initial checkout tests were performed at Barber- Nichols to ready the system for delivery to GRC. This presentation describes the system hardware components and lists the types of checkout tests performed along with a couple issues encountered while conducting the tests. A description of the CCSS model is also presented. The checkout tests did not focus on generating data, therefore, no test data or model analyses are presented.

  17. Optimal Spacing of Dual-axis Trackers for Concentrating Photovoltaic Systems

    NASA Astrophysics Data System (ADS)

    Kim, Yong Sin; Winston, Roland

    2011-12-01

    The levelized cost of energy (LCOE) is widely used to compare the cost of energy generation across technologies. In a utility-scale concentrating photovoltaic (CPV) system, the spacing of dual-axis trackers must be balanced with total energy harvested from modules to minimize LCOE. In this paper, a spacing method of dual-axis trackers in a CPV system is presented. Based on the definition of LCOE, a cost function is defined and optimized in terms of spacing related parameters. Various methods to estimate hourly direct normal irradiance (DNI) are investigated and m-by-n tracker array configurations to minimize the cost function are discussed.

  18. Dual manifold system and method for fluid transfer

    DOEpatents

    Doktycz, Mitchel J.; Bryan, William Louis; Kress, Reid

    2003-05-27

    A dual-manifold assembly is provided for the rapid, parallel transfer of liquid reagents from a microtiter plate to a solid state microelectronic device having biological sensors integrated thereon. The assembly includes aspiration and dispense manifolds connected by a plurality of conduits. In operation, the aspiration manifold is actuated such that the aspiration manifold is seated onto an array of reagent-filled wells of the microtiter plate. The wells are pressurized to force reagent through conduits toward the dispense manifold. A pressure pulse provided by a standard ink-jet printhead ejects nanoliter-to-picoliter droplets of reagent through an array of printhead orifices and onto test sites on the surface of the microelectronic device.

  19. Dual manifold system and method for fluid transfer

    DOEpatents

    Doktycz, Mitchel J.; Bryan, William Louis; Kress, Reid

    2003-09-30

    A dual-manifold assembly is provided for the rapid, parallel transfer of liquid reagents from a microtiter plate to a solid state microelectronic device having biological sensors integrated thereon. The assembly includes aspiration and dispense manifolds connected by a plurality of conduits. In operation, the aspiration manifold is actuated such that the aspiration manifold is seated onto an array of reagent-filled wells of the microtiter plate. The wells are pressurized to force reagent through conduits toward the dispense manifold. A pressure pulse provided by a standard ink-jet printhead ejects nanoliter-to-picoliter droplets of reagent through an array of printhead orifices and onto test sites on the surface of the microelectronic device.

  20. Effect of Operating Parameters on a Dual-Stage High Velocity Oxygen Fuel Thermal Spray System

    NASA Astrophysics Data System (ADS)

    Khan, Mohammed N.; Shamim, Tariq

    2014-08-01

    High velocity oxygen fuel (HVOF) thermal spray systems are being used to apply coatings to prevent surface degradation. The coatings of temperature sensitive materials such as titanium and copper, which have very low melting points, cannot be applied using a single-stage HVOF system. Therefore, a dual-stage HVOF system has been introduced and modeled computationally. The dual-spray system provides an easy control of particle oxidation by introducing a mixing chamber. In addition to the materials being sprayed, the thermal spray coating quality depends to a large extent on flow behavior of reacting gases and the particle dynamics. The present study investigates the influence of various operating parameters on the performance of a dual-stage thermal spray gun. The objective is to develop a predictive understanding of various parameters. The gas flow field and the free jet are modeled by considering the conservation of mass, momentum, and energy with the turbulence and the equilibrium combustion sub models. The particle phase is decoupled from the gas phase due to very low particle volume fractions. The results demonstrate the advantage of a dual-stage system over a single-stage system especially for the deposition of temperature sensitive materials.

  1. A dual-systems perspective on addiction: contributions from neuroimaging and cognitive training

    PubMed Central

    McClure, Samuel M.; Bickel, Warren K.

    2014-01-01

    Dual-systems theories explain lapses in self-control in terms of a conflict between automatic and deliberative modes of behavioral control. Numerous studies have now tested whether the brain areas that control behavior are organized in a manner consistent with dual-systems models. Brain regions directly associated with the mesolimbic dopamine system, the nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC) in particular, capture some of the features assumed by automatic processing. Regions in the lateral prefrontal cortex (lPFC) are more closely linked to deliberative processing and the exertion of self-control in the suppression of impulses. While identifying these regions crudely supports dual-system theories, important modifications to what constitutes automatic and deliberative behavioral control are also suggested. Experiments have identified various means by which automatic processes may be sculpted. Additional work decomposes deliberative processes into component functions such as generalized working memory, reappraisal of emotional stimuli, and prospection. The importance of deconstructing dual-systems models into specific cognitive processes is clear for understanding and treating addiction. We discuss intervention possibilities suggested by recent research, and focus in particular on cognitive training approaches to bolster deliberative control processes that may aid quit attempts. PMID:25336389

  2. A dual-systems perspective on addiction: contributions from neuroimaging and cognitive training.

    PubMed

    McClure, Samuel M; Bickel, Warren K

    2014-10-01

    Dual-systems theories explain lapses in self-control in terms of a conflict between automatic and deliberative modes of behavioral control. Numerous studies have now tested whether the brain areas that control behavior are organized in a manner consistent with dual-systems models. Brain regions directly associated with the mesolimbic dopamine system, the nucleus accumbens and ventromedial prefrontal cortex in particular, capture some of the features assumed by automatic processing. Regions in the lateral prefrontal cortex are more closely linked to deliberative processing and the exertion of self-control in the suppression of impulses. While identifying these regions crudely supports dual-systems theories, important modifications to what constitutes automatic and deliberative behavioral control are also suggested. Experiments have identified various means by which automatic processes may be sculpted. Additional work decomposes deliberative processes into component functions such as generalized working memory, reappraisal of emotional stimuli, and prospection. The importance of deconstructing dual-systems models into specific cognitive processes is clear for understanding and treating addiction. We discuss intervention possibilities suggested by recent research, and focus in particular on cognitive training approaches to bolster deliberative control processes that may aid quit attempts. PMID:25336389

  3. A novel dual-frequency loading system for studying mechanobiology of load-bearing tissue.

    PubMed

    Zhang, Chunqiu; Qiu, Lulu; Gao, Lilan; Guan, Yinjie; Xu, Qiang; Zhang, Xizheng; Chen, Qian

    2016-12-01

    In mechanobiological research, an appropriate loading system is an essential tool to mimic mechanical signals in a native environment. To achieve this goal, we have developed a novel loading system capable of applying dual-frequency loading including both a low-frequency high-amplitude loading and a high-frequency low-amplitude loading, according to the mechanical conditions experienced by bone and articular cartilage tissues. The low-frequency high-amplitude loading embodies the main force from muscular contractions and/or reaction forces while the high-frequency low-amplitude loading represents an assistant force from small muscles, ligaments and/or other tissue in order to maintain body posture during human activities. Therefore, such dual frequency loading system may reflect the natural characteristics of complex mechanical load on bone or articular cartilage than the single frequency loading often applied during current mechanobiological experiments. The dual-frequency loading system is validated by experimental tests using precision miniature plane-mirror interferometers. The dual-frequency loading results in significantly more solute transport in articular cartilage than that of the low-frequency high-amplitude loading regiment alone, as determined by quantitative fluorescence microscopy of tracer distribution in articular cartilage. Thus, the loading system can provide a new method to mimic mechanical environment in bone and cartilage, thereby revealing the in vivo mechanisms of mechanosensation, mechanotransduction and mass-transport, and improving mechanical conditioning of cartilage and/or bone constructs for tissue engineering. PMID:27612712

  4. A dual-systems perspective on addiction: contributions from neuroimaging and cognitive training.

    PubMed

    McClure, Samuel M; Bickel, Warren K

    2014-10-01

    Dual-systems theories explain lapses in self-control in terms of a conflict between automatic and deliberative modes of behavioral control. Numerous studies have now tested whether the brain areas that control behavior are organized in a manner consistent with dual-systems models. Brain regions directly associated with the mesolimbic dopamine system, the nucleus accumbens and ventromedial prefrontal cortex in particular, capture some of the features assumed by automatic processing. Regions in the lateral prefrontal cortex are more closely linked to deliberative processing and the exertion of self-control in the suppression of impulses. While identifying these regions crudely supports dual-systems theories, important modifications to what constitutes automatic and deliberative behavioral control are also suggested. Experiments have identified various means by which automatic processes may be sculpted. Additional work decomposes deliberative processes into component functions such as generalized working memory, reappraisal of emotional stimuli, and prospection. The importance of deconstructing dual-systems models into specific cognitive processes is clear for understanding and treating addiction. We discuss intervention possibilities suggested by recent research, and focus in particular on cognitive training approaches to bolster deliberative control processes that may aid quit attempts.

  5. A novel dual-frequency loading system for studying mechanobiology of load-bearing tissue.

    PubMed

    Zhang, Chunqiu; Qiu, Lulu; Gao, Lilan; Guan, Yinjie; Xu, Qiang; Zhang, Xizheng; Chen, Qian

    2016-12-01

    In mechanobiological research, an appropriate loading system is an essential tool to mimic mechanical signals in a native environment. To achieve this goal, we have developed a novel loading system capable of applying dual-frequency loading including both a low-frequency high-amplitude loading and a high-frequency low-amplitude loading, according to the mechanical conditions experienced by bone and articular cartilage tissues. The low-frequency high-amplitude loading embodies the main force from muscular contractions and/or reaction forces while the high-frequency low-amplitude loading represents an assistant force from small muscles, ligaments and/or other tissue in order to maintain body posture during human activities. Therefore, such dual frequency loading system may reflect the natural characteristics of complex mechanical load on bone or articular cartilage than the single frequency loading often applied during current mechanobiological experiments. The dual-frequency loading system is validated by experimental tests using precision miniature plane-mirror interferometers. The dual-frequency loading results in significantly more solute transport in articular cartilage than that of the low-frequency high-amplitude loading regiment alone, as determined by quantitative fluorescence microscopy of tracer distribution in articular cartilage. Thus, the loading system can provide a new method to mimic mechanical environment in bone and cartilage, thereby revealing the in vivo mechanisms of mechanosensation, mechanotransduction and mass-transport, and improving mechanical conditioning of cartilage and/or bone constructs for tissue engineering.

  6. Three dimensional laser microfabrication in diamond using a dual adaptive optics system.

    PubMed

    Simmonds, Richard D; Salter, Patrick S; Jesacher, Alexander; Booth, Martin J

    2011-11-21

    Femtosecond laser fabrication of controlled three dimensional structures deep in the bulk of diamond is facilitated by a dual adaptive optics system. A deformable mirror is used in parallel with a liquid crystal spatial light modulator to compensate the extreme aberrations caused by the refractive index mismatch between the diamond and the objective immersion medium. It is shown that aberration compensation is essential for the generation of controlled micron-scale features at depths greater than 200 μm, and the dual adaptive optics approach demonstrates increased fabrication efficiency relative to experiments using a single adaptive element. PMID:22109438

  7. Removal of ammonia from urine vapor by a dual-catalyst system

    NASA Technical Reports Server (NTRS)

    Budininkas, P.

    1977-01-01

    The feasibility of removing ammonia from urine vapor by a low-temperature dual-catalyst system has been demonstrated. The process is based on the catalytic oxidation of ammonia to a mixture of nitrogen, nitrous oxide, and water, followed by a catalytic decomposition of the nitrous oxide into its elements. Potential ammonia oxidation and nitrous oxide decomposition catalysts were first screened with artificial gas mixtures, then tested with the actual urine vapor produced by boiling untreated urine. A suitable dual-catalyst bed arrangement was found that achieved the removal of ammonia and also organic carbon, and recovered water of good quality from urine vapor.

  8. Quantum interference of stored dual-channel spin-wave excitations in a single tripod system

    SciTech Connect

    Wang Hai; Li Shujing; Xu Zhongxiao; Zhao Xingbo; Zhang Lijun; Li Jiahua; Wu Yuelong; Xie Changde; Peng Kunchi; Xiao Min

    2011-04-15

    We present an experimental demonstration of dual-channel memory in a single tripod atomic system. The total readout signal exhibits either constructive or destructive interference when the dual-channel spin-wave excitations (SWEs) are retrieved by two reading beams with a controllable relative phase. When the two reading beams have opposite phases, the SWEs will remain in the medium, which can be retrieved later with two in-phase reading beams. Such a phase-sensitive storage and retrieval scheme can be used to measure and control the relative phase between the two SWEs in the memory medium, which may find applications in quantum-information processing.

  9. The Problem of Cultural Fit--What Can We Learn from Borrowing the German Dual System?

    ERIC Educational Resources Information Center

    Lewis, Theodore

    2007-01-01

    Culture impedes educational transactions between developed countries, and is often an area of tension when developing countries try to borrow models, or have models imposed upon them. This article uses the German Dual System as a case for examining issues surrounding the adaptation of borrowed models. Since attempts at borrowing models can fail…

  10. Dual Water Systems: Characterization and Performance for Distribution of Reclaimed Water (WaterRF Report 4333)

    EPA Science Inventory

    The research tasks included: an inventory of cases where dual systems have been implemented; formulation of a protocol to identify claimed benefits, costs, and risks; collection of data (quantitative and anecdotal) to assess performance; display of data in the form of performance...

  11. Diversity of free-living amoebae in a dual distribution (potable and recycled) water system

    EPA Science Inventory

    Free-living amoebae are known to facilitate the growth of water associated pathogens. This study, for the first time, explored the diversity of free-living amoebae in a dual distribution (potable and recycled) water system in Rouse Hill NSW, Australia. Water and biofilm samples w...

  12. 14 CFR 105.43 - Use of single-harness, dual-parachute systems.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Use of single-harness, dual-parachute systems. 105.43 Section 105.43 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF... from mold, mildew, and other fungi, and other rotting agents propagated in a moist environment; or...

  13. 14 CFR 105.43 - Use of single-harness, dual-parachute systems.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Use of single-harness, dual-parachute systems. 105.43 Section 105.43 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF... from mold, mildew, and other fungi, and other rotting agents propagated in a moist environment; or...

  14. The Emerging Roles of Coaches in the Malaysian Dual Training System

    ERIC Educational Resources Information Center

    Othman, Ahmad; Abdullah, Nor Hazana; Sulaiman, Mohamad; Shamsuddin, Alina

    2011-01-01

    This paper discusses the new task of industry personnel as coaches in the National Dual Training System (NDTS), a newly introduced training initiative for producing k-workers in Malaysia. The decision to introduce this initiative was made by the Malaysian Cabinet on the 19th May 2004 with the hope that it will resolve the issue of skilled workers…

  15. A low-cost dual-camera imaging system for aerial applicators

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Agricultural aircraft provide a readily available remote sensing platform as low-cost and easy-to-use consumer-grade cameras are being increasingly used for aerial imaging. In this article, we report on a dual-camera imaging system we recently assembled that can capture RGB and near-infrared (NIR) i...

  16. Development of the Dual Aerodynamic Nozzle Model for the NTF Semi-Span Model Support System

    NASA Technical Reports Server (NTRS)

    Jones, Greg S.; Milholen, William E., II; Goodliff, Scott L.

    2011-01-01

    The recent addition of a dual flow air delivery system to the NASA Langley National Transonic Facility was experimentally validated with a Dual Aerodynamic Nozzle semi-span model. This model utilized two Stratford calibration nozzles to characterize the weight flow system of the air delivery system. The weight flow boundaries for the air delivery system were identified at mildly cryogenic conditions to be 0.1 to 23 lbm/sec for the high flow leg and 0.1 to 9 lbm/sec for the low flow leg. Results from this test verified system performance and identified problems with the weight-flow metering system that required the vortex flow meters to be replaced at the end of the test.

  17. A dual cone-beam CT system for image guided radiotherapy: Initial performance characterization

    SciTech Connect

    Li Hao; Bowsher, James; Yin Fangfang; Giles, William

    2013-02-15

    Purpose: The purpose of this study is to evaluate the performance of a recently developed benchtop dual cone-beam computed tomography (CBCT) system with two orthogonally placed tube/detector sets. Methods: The benchtop dual CBCT system consists of two orthogonally placed 40 Multiplication-Sign 30 cm flat-panel detectors and two conventional x-ray tubes with two individual high-voltage generators sharing the same rotational axis. The x-ray source to detector distance is 150 cm and x-ray source to rotational axis distance is 100 cm for both subsystems. The objects are scanned through 200 Degree-Sign of rotation. The dual CBCT system utilized 110 Degree-Sign of projection data from one detector and 90 Degree-Sign from the other while the two individual single CBCTs utilized 200 Degree-Sign data from each detector. The system performance was characterized in terms of uniformity, contrast, spatial resolution, noise power spectrum, and CT number linearity. The uniformities, within the axial slice and along the longitudinal direction, and noise power spectrum were assessed by scanning a water bucket; the contrast and CT number linearity were measured using the Catphan phantom; and the spatial resolution was evaluated using a tungsten wire phantom. A skull phantom and a ham were also scanned to provide qualitative evaluation of high- and low-contrast resolution. Each measurement was compared between dual and single CBCT systems. Results: Compared to single CBCT, the dual CBCT presented: (1) a decrease in uniformity by 1.9% in axial view and 1.1% in the longitudinal view, as averaged for four energies (80, 100, 125, and 150 kVp); (2) comparable or slightly better contrast (0{approx}25 HU) for low-contrast objects and comparable contrast for high-contrast objects; (3) comparable spatial resolution; (4) comparable CT number linearity with R{sup 2}{>=} 0.99 for all four tested energies; (5) lower noise power spectrum in magnitude. Dual CBCT images of the skull phantom and the

  18. An image quality comparison of standard and dual-side read CR systems for pediatric radiology

    SciTech Connect

    Monnin, P.; Holzer, Z.; Wolf, R.; Neitzel, U.; Vock, P.; Gudinchet, F.; Verdun, F.R.

    2006-02-15

    An objective analysis of image quality parameters was performed for a computed radiography (CR) system using both standard single-side and prototype dual-side read plates. The pre-sampled modulation transfer function (MTF), noise power spectrum (NPS), and detective quantum efficiency (DQE) for the systems were determined at three different beam qualities representative of pediatric chest radiography, at an entrance detector air kerma of 5 {mu}Gy. The NPS and DQE measurements were realized under clinically relevant x-ray spectra for pediatric radiology, including x-ray scatter radiations. Compared to the standard single-side read system, the MTF for the dual-side read system is reduced, but this is offset by a significant decrease in image noise, resulting in a marked increase in DQE (+40%) in the low spatial frequency range. Thus, for the same image quality, the new technology permits the CR system to be used at a reduced dose level.

  19. Tests of a Dual-systems Model of Speech Category Learning

    PubMed Central

    Maddox, W. Todd; Chandrasekaran, Bharath

    2013-01-01

    In the visual domain, more than two decades of work posits the existence of dual category learning systems. The reflective system uses working memory to develop and test rules for classifying in an explicit fashion. The reflexive system operates by implicitly associating perception with actions that lead to reinforcement. Dual-systems models posit that in learning natural categories, learners initially use the reflective system and with practice, transfer control to the reflexive system. The role of reflective and reflexive systems in second language (L2) speech learning has not been systematically examined. Here monolingual, native speakers of American English were trained to categorize Mandarin tones produced by multiple talkers. Our computational modeling approach demonstrates that learners use reflective and reflexive strategies during tone category learning. Successful learners use talker-dependent, reflective analysis early in training and reflexive strategies by the end of training. Our results demonstrate that dual-learning systems are operative in L2 speech learning. Critically, learner strategies directly relate to individual differences in category learning success. PMID:25264426

  20. Arrested development? Reconsidering dual-systems models of brain function in adolescence and disorders

    PubMed Central

    Pfeifer, Jennifer H.; Allen, Nicholas B.

    2012-01-01

    The dual-systems model of a ventral affective system, whose reactivity confers risks and liabilities, and a prefrontal control system, whose regulatory capacities buffer against these vulnerabilities, is an intuitive account that pervades many fields in the cognitive neurosciences – especially in the study of populations that differ from neurotypical adults, such as adolescents or individuals with affective or impulse regulation disorders. However, recent evidence that is inconsistent with dual-systems models illustrates the complexity of developmental and clinical variations in brain function. Building new models to account for this complexity is critical to progress in these fields, and will be facilitated by research that emphasizes network-based approaches and maps relationships between structure and function, as well as brain and behavior, over time. PMID:22613872

  1. Comparison between single- and dual-electrode ion source systems for low-energy ion transport

    SciTech Connect

    Vasquez, M. Jr.; Tokumura, S.; Kasuya, T.; Maeno, S.; Wada, M.

    2012-11-06

    Extraction of ions with energies below 100 eV has been demonstrated using a hot-cathode multi-cusp ion source equipped with extraction electrodes made of thin wires. Two electrode geometries, a single-electrode system, and a dual-electrode system were built and tested. The single-electrode configuration showed high ion beam current densities at shorter distances from the electrode but exhibited rapid attenuation as the distance from the electrode increased. Beam angular spread measurements showed similar beam divergence for both electrode configurations at low plasma densities. At high plasma densities and low extraction potentials, the single-electrode system showed the angular spread twice as large as that of the dual-electrode system. Energy distribution analyses showed a broader energy spread for ion beams extracted from a single-electrode set-up.

  2. Effects of mixing system and pilot fuel quality on diesel-biogas dual fuel engine performance.

    PubMed

    Bedoya, Iván Darío; Arrieta, Andrés Amell; Cadavid, Francisco Javier

    2009-12-01

    This paper describes results obtained from CI engine performance running on dual fuel mode at fixed engine speed and four loads, varying the mixing system and pilot fuel quality, associated with fuel composition and cetane number. The experiments were carried out on a power generation diesel engine at 1500 m above sea level, with simulated biogas (60% CH(4)-40% CO(2)) as primary fuel, and diesel and palm oil biodiesel as pilot fuels. Dual fuel engine performance using a naturally aspirated mixing system and diesel as pilot fuel was compared with engine performance attained with a supercharged mixing system and biodiesel as pilot fuel. For all loads evaluated, was possible to achieve full diesel substitution using biogas and biodiesel as power sources. Using the supercharged mixing system combined with biodiesel as pilot fuel, thermal efficiency and substitution of pilot fuel were increased, whereas methane and carbon monoxide emissions were reduced.

  3. Effects of mixing system and pilot fuel quality on diesel-biogas dual fuel engine performance.

    PubMed

    Bedoya, Iván Darío; Arrieta, Andrés Amell; Cadavid, Francisco Javier

    2009-12-01

    This paper describes results obtained from CI engine performance running on dual fuel mode at fixed engine speed and four loads, varying the mixing system and pilot fuel quality, associated with fuel composition and cetane number. The experiments were carried out on a power generation diesel engine at 1500 m above sea level, with simulated biogas (60% CH(4)-40% CO(2)) as primary fuel, and diesel and palm oil biodiesel as pilot fuels. Dual fuel engine performance using a naturally aspirated mixing system and diesel as pilot fuel was compared with engine performance attained with a supercharged mixing system and biodiesel as pilot fuel. For all loads evaluated, was possible to achieve full diesel substitution using biogas and biodiesel as power sources. Using the supercharged mixing system combined with biodiesel as pilot fuel, thermal efficiency and substitution of pilot fuel were increased, whereas methane and carbon monoxide emissions were reduced. PMID:19683439

  4. Dual-Use Aspects of System Health Management

    NASA Technical Reports Server (NTRS)

    Owens, P. R.; Jambor, B. J.; Eger, G. W.; Clark, W. A.

    1994-01-01

    System Health Management functionality is an essential part of any space launch system. Health management functionality is an integral part of mission reliability, since it is needed to verify the reliability before the mission starts. Health Management is also a key factor in life cycle cost reduction and in increasing system availability. The degree of coverage needed by the system and the degree of coverage made available at a reasonable cost are critical parameters of a successful design. These problems are not unique to the launch vehicle world. In particular, the Intelligent Vehicle Highway System, commercial aircraft systems, train systems, and many types of industrial production facilities require various degrees of system health management. In all of these applications, too, the designers must balance the benefits and costs of health management in order to optimize costs. The importance of an integrated system is emphasized. That is, we present the case for considering health management as an integral part of system design, rather than functionality to be added on at the end of the design process. The importance of maintaining the system viewpoint is discussed in making hardware and software tradeoffs and in arriving at design decisions. We describe an approach to determine the parameters to be monitored in any system health management application. This approach is based on Design of Experiments (DOE), prototyping, failure modes and effects analyses, cost modeling and discrete event simulation. The various computer-based tools that facilitate the approach are discussed. The approach described originally was used to develop a fault tolerant avionics architecture for launch vehicles that incorporated health management as an integral part of the system. Finally, we discuss generalizing the technique to apply it to other domains. Several illustrations are presented.

  5. DC Self Bias Trends in Dual Frequency PECVD Deposition Systems

    NASA Astrophysics Data System (ADS)

    Keil, D. L.; Augustyniak, E.; Leeser, C.; Galli, F.

    2011-10-01

    Capacitively coupled plasma (CCP) etch systems commonly report the DC auto or self bias developed as a consequence of capacitively coupling RF to the plasma. Frequently, these systems employ wafer pedestals comprised of electrostatic chucks which must monitor the self bias as part of their normal operation. DC self bias is often found to correlate with various etch process behaviors or system states. It is less common, however, to find CCP deposition systems that report DC self bias. This work reports results of a study of DC self bias trends due to chamber pressure, chamber conditioning and aging, and changes in wafer pedestal hardware. In particular, chamber film accumulation is found to correlate to certain DC bias trends. The applicability of these results for process tracking and system monitoring is discussed. Additionally, the DC self bias response to deliberate perturbations to the RF system are examined. These perturbations include those not normally encountered during commercial deposition such as `bleeding' current to ground.

  6. Dual objective active suspension system based on a novel nonlinear disturbance compensator

    NASA Astrophysics Data System (ADS)

    Deshpande, Vaijayanti S.; Shendge, P. D.; Phadke, S. B.

    2016-09-01

    This paper proposes an active suspension system to fulfil the dual objective of improving ride comfort while trying to keep the suspension deflection within the limits of the rattle space. The scheme is based on a novel nonlinear disturbance compensator which employs a nonlinear function of the suspension deflection. The scheme is analysed and validated by simulation and experimentation on a laboratory setup. The performance is compared with a passive suspension system for a variety of road profiles.

  7. Dual-mode microwave system to enhance early detection of cancer

    NASA Technical Reports Server (NTRS)

    Carr, K. L.; El-Mahdi, A. M.; Shaeffer, J.

    1981-01-01

    A dual-mode microwave system has been developed that will permit early detection of cancer. The system combines the use of the passive microwave radiometer with an active transmitter. The active transmitter will provide localized heating to enhance early detection by taking advantage of the differential heating (i.e., tumor temperature with respect to surrounding tissue) associated with the thermal characteristics of tumors.

  8. Development of an ESR/MR dual-imaging system as a tool to detect bioradicals.

    PubMed

    Fujii, Hirotada; Aoki, Masaaki; Haishi, Tomoyuki; Itoh, Kouichi; Sakata, Motomichi

    2006-04-01

    A system combining electron spin resonance imaging (ESRI) with another imaging modality capable of enabling visualization of the distribution of bioradicals on an anatomical map of the specimens would be a superior biomedical imaging system. We describe the development of an ESR/MR dual-imaging system with one permanent magnet and the biomedical applications of this system. The magnetic circuit developed for the ESR/MR dual-imaging system consisted of the permanent magnet made of Fe-Nd-B, pole pieces, and poke. The permanent magnet was installed on the MR side only, and the ESR side was made of pole pieces only. The magnetic field was adjusted to 0.5T at MR and to 0.042T at ESR. The overall dimensions of the magnet developed for the ESR/MR imaging system were 460 (W)x440 (D)x460 (H) mm, and it weighed 220 kg. The distance of each center for the magnet for ESR and MR imaging could be set as close as 200 mm. The entire ESR/MR imaging system can be installed in a common laboratory without magnetic shielding. MR images of plants (myoga) and small animals (mice and rats) were successfully acquired with or without ESR operation. ESR spectra of nitroxyl spin probes were also measured, even with MRI operation. ESR signals of triarylmethyl derivatives with narrow line-width (0.026 mT) were observed in living mice while MRI was operating. The ESR/MR imaging dual functions work properly with no electric or magnetic interference. The ESR/MR dual images demonstrate that this system enables visualization of the distribution of bioradicals on the anatomical map of the object.

  9. Design of a dual port volume measuring system

    SciTech Connect

    Klevgard, P.A.

    1990-09-01

    A volume measuring system is described which uses the ideal gas law and pressure measurements to determine an unknown vessel's volume when a gas expands into that vessel from a known volume. The design, the engineering principles, the calibration, and the accuracy of this computer-controlled system are all discussed. A set of electrical and mechanical drawings of the system is included. 3 refs., 6 figs.

  10. System-Level Logistics for Dual Purpose Canister Disposal

    SciTech Connect

    Kalinina, Elena A.

    2014-06-03

    The analysis presented in this report investigated how the direct disposal of dual purpose canisters (DPCs) may be affected by the use of standard transportation aging and disposal canisters (STADs), early or late start of the repository, and the repository emplacement thermal power limits. The impacts were evaluated with regard to the availability of the DPCs for emplacement, achievable repository acceptance rates, additional storage required at an interim storage facility (ISF) and additional emplacement time compared to the corresponding repackaging scenarios, and fuel age at emplacement. The result of this analysis demonstrated that the biggest difference in the availability of UNF for emplacement between the DPC-only loading scenario and the DPCs and STADs loading scenario is for a repository start date of 2036 with a 6 kW thermal power limit. The differences are also seen in the availability of UNF for emplacement between the DPC-only loading scenario and the DPCs and STADs loading scenario for the alternative with a 6 kW thermal limit and a 2048 start date, and for the alternatives with a 10 kW thermal limit and 2036 and 2048 start dates. The alternatives with disposal of UNF in both DPCs and STADs did not require additional storage, regardless of the repository acceptance rate, as compared to the reference repackaging case. In comparison to the reference repackaging case, alternatives with the 18 kW emplacement thermal limit required little to no additional emplacement time, regardless of the repository start time, the fuel loading scenario, or the repository acceptance rate. Alternatives with the 10 kW emplacement thermal limit and the DPCs and STADs fuel loading scenario required some additional emplacement time. The most significant decrease in additional emplacement time occurred in the alternative with the 6 kW thermal limit and the 2036 repository starting date. The average fuel age at emplacement ranges from 46 to 88 years. The maximum fuel age at

  11. Adaptive optics ophthalmologic systems using dual deformable mirrors

    SciTech Connect

    Jones, S; Olivier, S; Chen, D; Sadda, S; Joeres, S; Zawadzki, R; Werner, J S; Miller, D

    2007-02-01

    Adaptive Optics (AO) have been increasingly combined with a variety of ophthalmic instruments over the last decade to provide cellular-level, in-vivo images of the eye. The use of MEMS deformable mirrors in these instruments has recently been demonstrated to reduce system size and cost while improving performance. However, currently available MEMS mirrors lack the required range of motion for correcting large ocular aberrations, such as defocus and astigmatism. In order to address this problem, we have developed an AO system architecture that uses two deformable mirrors, in a woofer/tweeter arrangement, with a bimorph mirror as the woofer and a MEMS mirror as the tweeter. This setup provides several advantages, including extended aberration correction range, due to the large stroke of the bimorph mirror, high order aberration correction using the MEMS mirror, and additionally, the ability to ''focus'' through the retina. This AO system architecture is currently being used in four instruments, including an Optical Coherence Tomography (OCT) system and a retinal flood-illuminated imaging system at the UC Davis Medical Center, a Scanning Laser Ophthalmoscope (SLO) at the Doheny Eye Institute, and an OCT system at Indiana University. The design, operation and evaluation of this type of AO system architecture will be presented.

  12. Action, outcome, and value: a dual-system framework for morality.

    PubMed

    Cushman, Fiery

    2013-08-01

    Dual-system approaches to psychology explain the fundamental properties of human judgment, decision making, and behavior across diverse domains. Yet, the appropriate characterization of each system is a source of debate. For instance, a large body of research on moral psychology makes use of the contrast between "emotional" and "rational/cognitive" processes, yet even the chief proponents of this division recognize its shortcomings. Largely independently, research in the computational neurosciences has identified a broad division between two algorithms for learning and choice derived from formal models of reinforcement learning. One assigns value to actions intrinsically based on past experience, while another derives representations of value from an internally represented causal model of the world. This division between action- and outcome-based value representation provides an ideal framework for a dual-system theory in the moral domain.

  13. Three-Dimensional Display System with Dual-Frequency Liquid-Crystal Varifocal Lens

    NASA Astrophysics Data System (ADS)

    Suyama, Shiro; Date, Munekazu; Takada, Hideaki

    2000-02-01

    A new volumetric three-dimensional (3-D) display system that provides all the visual cues to depth perception has been developed. This system provides flicker-free, large 3-D images of 250 mm in both diameter and depth with a viewing cone from {-}10\\circ to {+}10\\circ. The system is simply composed of a dual-frequency liquid-crystal (LC) varifocal lens (the key device), a two-dimensional display, and two fixed lens. The focal length of the LC varifocal lens can be continuously varied from {-}1.2 to {+}1.5 diopters (1/m) by changing the effective refractive index of LC@. Using a dual-frequency LC for the varifocal lens achieves sufficiently fast operation of at least 60 Hz for flicker-free moving 3-D images. The simple structure of our varifocal lens facilitates the fabrication of a large-diameter lens, resulting in large 3-D images with a sufficient viewing cone.

  14. DualTrust: A Distributed Trust Model for Swarm-Based Autonomic Computing Systems

    SciTech Connect

    Maiden, Wendy M.; Dionysiou, Ioanna; Frincke, Deborah A.; Fink, Glenn A.; Bakken, David E.

    2011-02-01

    For autonomic computing systems that utilize mobile agents and ant colony algorithms for their sensor layer, trust management is important for the acceptance of the mobile agent sensors and to protect the system from malicious behavior by insiders and entities that have penetrated network defenses. This paper examines the trust relationships, evidence, and decisions in a representative system and finds that by monitoring the trustworthiness of the autonomic managers rather than the swarming sensors, the trust management problem becomes much more scalable and still serves to protect the swarm. We then propose the DualTrust conceptual trust model. By addressing the autonomic manager’s bi-directional primary relationships in the ACS architecture, DualTrust is able to monitor the trustworthiness of the autonomic managers, protect the sensor swarm in a scalable manner, and provide global trust awareness for the orchestrating autonomic manager.

  15. Considerations of a Dual-systems Model of Cognitive Development and Risky Driving

    PubMed Central

    Lambert, Ann E.; Simons-Morton, Bruce G.; Cain, Sarah A.; Weisz, Sarah; Cox, Daniel J.

    2014-01-01

    The dual-systems model of adolescent risk-taking postulates that risk-taking during adolescence partially results from an imbalance in the development of the executive and the socio-emotional cognitive systems. While supported by behavioral and neuroanatomical data, translational research linking the model with real-world driving or laboratory driving simulation is sparse. This paper discusses the model as it relates to adolescent driving and reviews empirical studies that have applied it in a driving-specific context. While, the studies reviewed provided partial support, each lacked a critical component necessary to fully test the model. Thus, a strong test has yet to be implemented; however, the dual-systems model holds promise for advancing the understanding of teen driving risk and guiding applications for prevention and policy. PMID:25983529

  16. Development of a Dual-PIV system for high-speed flow applications

    NASA Astrophysics Data System (ADS)

    Schreyer, Anne-Marie; Lasserre, Jean J.; Dupont, Pierre

    2015-10-01

    A new Dual-particle image velocimetry (Dual-PIV) system for application in supersonic flows was developed. The system was designed for shock wave/turbulent boundary layer interactions with separation. This type of flow places demanding requirements on the system, from the large range of characteristic frequencies O(100 Hz-100 kHz) to spatial and temporal resolutions necessary for the measurement of turbulent quantities (Dolling in AIAA J 39(8):1517-1531, 2001; Dupont et al. in J Fluid Mech 559:255-277, 2006; Smits and Dussauge in Turbulent shear layers in supersonic flow, 2nd edn. Springer, New York, 2006). While classic PIV systems using high-resolution CCD sensors allow high spatial resolution, these systems cannot provide the required temporal resolution. Existing high-speed PIV systems provide temporal and CMOS sensor resolutions, and even laser pulse energies, that are not adapted to our needs. The only obvious solution allowing sufficiently high spatial resolution, access to high frequencies, and a high laser pulse energy is a multi-frame system: a Dual-PIV system, consisting of two synchronized PIV systems observing the same field of view, will give access to temporal characteristics of the flow. The key technology of our system is frequency-based image separation: two lasers of different wavelengths illuminate the field of view. The cross-pollution with laser light from the respective other branches was quantified during system validation. The overall system noise was quantified, and the prevailing error of only 2 % reflects the good spatial and temporal alignment. The quality of the measurement system is demonstrated with some results on a subsonic jet flow including the spatio-temporal inter-correlation functions between the systems. First measurements in a turbulent flat-plate boundary layer at Mach 2 show the same satisfactory data quality and are also presented and discussed.

  17. A CAD system based on spherical dual representations

    SciTech Connect

    Roach, J.W.; Paripati, P.K.; Wright, J.S.

    1987-08-01

    Computer-aided design (CAD) systems typically have many different functions: drafting, two-dimensional modeling, three-dimensional modeling, finite element analysis, and fit and tolerancing of parts. The authors report on the construction of a CAD system based on shape representation ideas used in the vision community to determine the shape of an object from its image. In the long term, they propose to construct a combined CAD and sensing system based on the same underlying object models. Considerable advantages follow from building a model-driven sensor fusion system that uses a common geometric model. In a manufacturing environment, for example, a library of objects can be built up and its models used in a vision and touch sensing system integrated into an automated assembly line to discriminate between objects and determine orientation and distance. If such a system could be made robust and highly reliable, then some of the most difficult problems that plague attempts to create a fully flexible automated environment would be solved.

  18. The development and performance evaluation of a dual stage ceramic foam filtration system

    SciTech Connect

    Aubrey, L.S.; Cummings, M.A.; Oliver, C.L.; Chow, M.

    1996-10-01

    The presence of non-metallic inclusions in aluminum billets can significantly affect both plastic deformation during the extrusion process and final surface quality. Traditionally, secondary extrusion billet casters have relied on a combination of furnace fluxing and a ceramic foam filter to obtain the required melt cleanliness. Ever increasing demands to obtain better extrusion surface quality and more complex shapes with reduced press cycle times, has led to a trend toward the use of finer pore ceramic foam filters. A dual stage filter bowl and preheat system has been developed which allows routine use of 50 ppi ceramic foam to filter metal produced from remelt scrap without the use of an in-line spinning nozzle degasser system. Improved metal cleanliness was quantified by taking LAIS inclusion samples prior to and after the installation of a dual stage filtration system. Overall, the filtration efficiency improved from 45--51% with a standard single stage ceramic foam filtration system to 85% with a dual stage system utilizing a 30 ppi/50 ppi filter pore size combination. Analysis of press cycle times indicated an overall reduction of 11.4% with AA 6061 billets. A 4.8% increase in extrusion press speed was realized with AA 7129 billets.

  19. Dual sensitivity mode system for monitoring processes and sensors

    DOEpatents

    Wilks, Alan D.; Wegerich, Stephan W.; Gross, Kenneth C.

    2000-01-01

    A method and system for analyzing a source of data. The system and method involves initially training a system using a selected data signal, calculating at least two levels of sensitivity using a pattern recognition methodology, activating a first mode of alarm sensitivity to monitor the data source, activating a second mode of alarm sensitivity to monitor the data source and generating a first alarm signal upon the first mode of sensitivity detecting an alarm condition and a second alarm signal upon the second mode of sensitivity detecting an associated alarm condition. The first alarm condition and second alarm condition can be acted upon by an operator and/or analyzed by a specialist or computer program.

  20. Computer-aided detection of breast masses on mammograms: performance improvement using a dual system

    NASA Astrophysics Data System (ADS)

    Wei, Jun; Sahiner, Berkman; Hadjiiski, Lubomir M.; Chan, Heang-Ping; Helvie, Mark A.; Roubidoux, Marilyn A.; Petrick, Nicholas; Ge, Jun; Zhou, Chuan

    2005-04-01

    We have developed a computer-aided detection (CAD) system for breast masses on mammograms. In this study, our purpose was to improve the performance of our mass detection system by using a new dual system approach which combines a CAD system optimized with "average" masses with another CAD system optimized with subtle masses. The latter system is trained to provide high sensitivity in detecting subtle masses. For an unknown mammogram, the two systems are used in parallel to detect suspicious objects. A feed-forward backpropagation neural network trained to merge the scores of the two linear discriminant analysis (LDA) classifiers from the two systems makes the final decision in differentiation of true masses from normal tissue. A data set of 86 patients containing 172 mammograms with biopsy-proven masses was partitioned into a training set and an independent test set. This data set is referred to as the average data set. A second data set of 214 prior mammograms was used for training the second CAD system for detection of subtle masses. When the single CAD system trained on the average data set was applied to the test set, the Az for false positive (FP) classification was 0.81 and the FP rates were 2.1, 1.5 and 1.3 FPs/image at the case-based sensitivities of 95%, 90% and 85%, respectively. With the dual CAD system, the Az was 0.85 and the FP rates were improved to 1.7, 1.2 and 0.8 FPs/image at the same case-based sensitivities. Our results indicate that the dual CAD system can improve the performance of mass detection on mammograms.

  1. Development of dual solid cryogens for high reliability refrigeration system

    NASA Technical Reports Server (NTRS)

    Caren, R. P.; Coston, R. M.

    1967-01-01

    High reliability solid cryogen refrigeration system consists of a container initially filled with a solid cryogen which is coupled thermally to an infrared detector by means of a link of high thermal conductivity extending from a heat exchanger within the cryogen container.

  2. Dual Source Mass Spectrometer and Sample Handling System

    NASA Technical Reports Server (NTRS)

    Brinckerhoff, W. B.; Mahaffy, P. R.; Cornish, T. J.; Cheng, A. F.; Niemann, H. B.; Harpold, D. N.; Gorevan, S. P.; Rafeek, S.; Yucht, D.

    2002-01-01

    We present details of a miniature integrated time-of-flight mass spectrometer and sample handling system under development to address some of the needs for in situ sample analysis on landed missions. Additional information is contained in the original extended abstract.

  3. Dual-row needle arrays under an electromagnetic thermotherapy system for bloodless liver resection surgery.

    PubMed

    Huang, Sheng Chieh; Chang, Yi Yuan; Chao, Ying Jui; Shan, Yan Shen; Lin, Xi Zhang; Lee, Gwo Bin

    2012-03-01

    Electromagnetic thermotherapy has been extensively investigated recently and may become a new surgical modality for a variety of medical applications. It applies a high-frequency alternating magnetic field to heat up magnetic materials inserted within the human body to generate tissue coagulation or cell apoptosis. Using a new procedure with dual-row needle arrays under an electromagnetic thermotherapy system with a feedback temperature control system, this study demonstrates bloodless porcine liver resection, which is challenging using existing methods. In vitro experiments showed that hollowed, stainless-steel needles could be heated up to more than 300 °C within 30 s when centered under the induction coils of the electromagnetic thermotherapy system. In order to generate a wide ablation zone and to prevent the dual-row needle arrays from sticking to the tissue after heating, a constant temperature of 120 °C was applied using a specific treatment protocol. The temperature distribution in the porcine livers was also measured to explore the effective coagulation area. Liver resection was then performed in Lan-Yu pigs. Experimental results showed that seven pigs underwent liver resection without bleeding during surgery and no complications afterward. The dual-row needle arrays combined with the electromagnetic thermotherapy system are thus shown to be promising for bloodless tissue resection.

  4. Dual-row needle arrays under an electromagnetic thermotherapy system for bloodless liver resection surgery.

    PubMed

    Huang, Sheng Chieh; Chang, Yi Yuan; Chao, Ying Jui; Shan, Yan Shen; Lin, Xi Zhang; Lee, Gwo Bin

    2012-03-01

    Electromagnetic thermotherapy has been extensively investigated recently and may become a new surgical modality for a variety of medical applications. It applies a high-frequency alternating magnetic field to heat up magnetic materials inserted within the human body to generate tissue coagulation or cell apoptosis. Using a new procedure with dual-row needle arrays under an electromagnetic thermotherapy system with a feedback temperature control system, this study demonstrates bloodless porcine liver resection, which is challenging using existing methods. In vitro experiments showed that hollowed, stainless-steel needles could be heated up to more than 300 °C within 30 s when centered under the induction coils of the electromagnetic thermotherapy system. In order to generate a wide ablation zone and to prevent the dual-row needle arrays from sticking to the tissue after heating, a constant temperature of 120 °C was applied using a specific treatment protocol. The temperature distribution in the porcine livers was also measured to explor