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Sample records for aldosterone antagonists

  1. Suppression of Aldosterone Synthesis and Secretion by Channel Antagonists

    Directory of Open Access Journals (Sweden)

    Keiichi Ikeda

    2012-01-01

    Full Text Available Aldosterone, a specific mineralocorticoid receptor (MR agonist and a key player in the development of hypertension, is synthesized as a final product of renin-angiotensin-aldosterone system. Hypertension can be generally treated by negating the effects of angiotensin II through the use of angiotensin-converting enzyme inhibitors (ACE-Is or angiotensin II type 1 receptor antagonists (ARBs. However, the efficacy of angiotensin II blockade by such drugs is sometimes diminished by the so-called “aldosterone breakthrough” effect, by which ACE-Is or ARBs (renin-angiotensin system (RAS inhibitors gradually lose their effectiveness against hypertension due to the overproduction of aldosterone, known as primary aldosteronism. Although MR antagonists are used to antagonize the effects of aldosterone, these drugs may, however, give rise to life-threatening adverse actions, such as hyperkalemia, particularly when used in conjunction with RAS inhibitors. Recently, several groups have reported that some dihydropyridine Ca2+ channel blockers (CCBs have inhibitory actions on aldosterone production in in vitro and in the clinical setting. Therefore, the use of such dihydropyridine CCBs to treat aldosterone-related hypertension may prove beneficial to circumvent such therapeutic problems. In this paper, we discuss the mechanism of action of CCBs on aldosterone production and clinical perspectives for CCB use to inhibit MR activity in hypertensive patients.

  2. Aldosterone receptor antagonists: current perspectives and therapies

    OpenAIRE

    Guichard JL; Clark III D; Calhoun DA; Ahmed MI

    2013-01-01

    Jason L Guichard, Donald Clark III, David A Calhoun, Mustafa I Ahmed University of Alabama at Birmingham, Department of Medicine, Division of Cardiovascular Disease, Vascular Biology and Hypertension Program, Birmingham, AL, USA Abstract: Aldosterone is a downstream effector of angiotensin II in the renin–angiotensin–aldosterone system and binds to the mineralocorticoid receptor. The classical view of aldosterone primarily acting at the level of the kidneys to regulate pl...

  3. Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure

    Directory of Open Access Journals (Sweden)

    Nappi J

    2011-06-01

    Full Text Available Jean M Nappi, Adam SiegClinical Pharmacy and Outcome Sciences, South Carolina College of Pharmacy, Medical University of South Carolina Campus, Charleston, SC, USAAbstract: Aldosterone is a mineralocorticoid hormone synthesized by the adrenal glands that has several regulatory functions to help the body maintain normal volume status and electrolyte balance. Studies have shown significantly higher levels of aldosterone secretion in patients with congestive heart failure compared with normal patients. Elevated levels of aldosterone have been shown to elevate blood pressure, cause left ventricular hypertrophy, and promote cardiac fibrosis. An appreciation of the true role of aldosterone in patients with chronic heart failure did not become apparent until the publication of the Randomized Aldactone Evaluation Study. Until recently, the use of aldosterone receptor antagonists has been limited to patients with severe heart failure and patients with heart failure following myocardial infarction. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF study added additional evidence to support the expanded use of aldosterone receptor antagonists in heart failure patients. The results of the EMPHASIS-HF trial showed that patients with mild-to-moderate (New York Heart Association Class II heart failure had reductions in mortality and hospitalizations from the addition of eplerenone to optimal medical therapy. Evidence remains elusive about the exact mechanism by which aldosterone receptor antagonists improve heart failure morbidity and mortality. The benefits of aldosterone receptor antagonist use in heart failure must be weighed against the potential risk of complications, ie, hyperkalemia and, in the case of spironolactone, possible endocrine abnormalities, in particular gynecomastia. With appropriate monitoring, these risks can be minimized. We now have evidence that patients with mild-to-severe symptoms

  4. SP 01-3 ALDOSTERONE ANTAGONISTS IN HEART FAILURE.

    Science.gov (United States)

    Johnston, Colin

    2016-09-01

    Aldosterone's deleterious pathophysiological effects on the cardiovascular system if blocked by mineralcorticord antagonists (MRAs) logically should lead to improvement in heart function and outcomes in heart failure (HF). The first trial to test this hypothesis was tthe RALES trial in 1999 which treated patients with class III-IV HF with spironolactone. It showed significant reduction in mortality and cardiovascular hospitalzation rates. This was confirmed & extended in EMHASIS-HF RCT with classs II-III being treated with ACEIs & BB who received placebo or elperinone (a MRA) with again a statistically significant fall in mortality & hospitalization.The possible cardioprotective effects of MRA post acute myocardial infarct (MI) is less clear. The EPHESUS RCT in 2003 demostrated that elperinone given 3-14 days AMI in patients with early signs of HF reduced mortality & morbidity. However in the ALBTROSS trial using spironolactone 2 days after AMI showed no benfit in patients without HF but in a subgroup with ST elevation there was a 80% reduction in mortality after 6 months. However a recent meta-analysis from 25 RCT with data invovling 19,333 patients with either HF or post MI assigned aldosterone antagonists (AA)or placebo showed a 18% reduction in mortality including a 20% fall in CV mortality and a 19% reduction in SCD.The role of AA in HFPEF is even even more contraversial. The TOPCAT RCT of 3445 patients with symptomatc HFPEF randomised to spironolactone failed to meet the primary composite end point of death, aborted cardiac arrest or hospitalization although there was a reduction in hospitalization for HF (HR 0.83 P = 0.04).The differences between selective or non-selective MRAs, their ADRs & off target effects will also be discussed.

  5. Long-term use of aldosterone-receptor antagonists in uncontrolled hypertension: A retrospective analysis

    NARCIS (Netherlands)

    P.M. Jansen (Pieter); K. Verdonk (Koen); B.P. Imholz (Ben); A.H.J. Danser (Jan); A.H. van den Meiracker (Anton)

    2011-01-01

    textabstractBackground. The long-term efficacy of aldosterone-receptor antagonists (ARAs) as add-on treatment in uncontrolled hypertension has not yet been reported. Methods. Data from 123 patients (21 with primary aldosteronism, 102 with essential hypertension) with difficult-to-treat hypertension

  6. Effects of treatment with β-blocker and aldosterone antagonist on central and peripheral haemodynamics and oxygenation in cirrhosis

    DEFF Research Database (Denmark)

    Winkler, Christine; Hobolth, Lise; Krag, Aleksander

    2011-01-01

    Patients with cirrhosis often exhibit abnormalities in cardiovascular regulation and oxygenation. Many of these patients are treated with β-blockers and aldosterone antagonists that may influence the regulation of systemic haemodynamics, but the specific effects on systemic haemodynamics and oxyg......Patients with cirrhosis often exhibit abnormalities in cardiovascular regulation and oxygenation. Many of these patients are treated with β-blockers and aldosterone antagonists that may influence the regulation of systemic haemodynamics, but the specific effects on systemic haemodynamics...

  7. Effects of treatment with β-blocker and aldosterone antagonist on central and peripheral haemodynamics and oxygenation in cirrhosis

    DEFF Research Database (Denmark)

    Winkler, Christine; Hobolth, Lise; Krag, Aleksander;

    2011-01-01

    Patients with cirrhosis often exhibit abnormalities in cardiovascular regulation and oxygenation. Many of these patients are treated with ß-blockers and aldosterone antagonists that may influence the regulation of systemic haemodynamics, but the specific effects on systemic haemodynamics and oxyg......Patients with cirrhosis often exhibit abnormalities in cardiovascular regulation and oxygenation. Many of these patients are treated with ß-blockers and aldosterone antagonists that may influence the regulation of systemic haemodynamics, but the specific effects on systemic haemodynamics...

  8. [Effect of combined treatment with dopamine receptor agonists and antagonists of aldosterone on the performance of daily blood pressure monitoring in patients with hypertension and concomitant obesity].

    Science.gov (United States)

    Lyzogub, V G; Sobol', V O; Dolynna, O V; Kuz'mins'ka, L A

    2012-01-01

    In hypertensive patients with concomitant obesity observed decrease in activity of dopaminergic system in conjunction with increased activity of the renin-angiotensin-aldosterone system. Identified changes point to the advisability of appointing this group of patients the dopamine receptor agonist - bromocriptine-KV and antagonist of aldosterone - veroshpiron. As a result of treatment was an increase in dopamine levels in the urine, a decrease of aldosterone in the blood, normalization of the daily blood pressure monitoring.

  9. Antagonistic effects of aldosterone on corticosterone-mediated changes in exploratory behavior of adrenalectomized rats

    NARCIS (Netherlands)

    Veldhuis, H D; De Kloet, E R

    1983-01-01

    The effect of aldosterone administration on exploratory activity of chronic adrenalectomized (10 days) male rats was investigated. Aldosterone (30 micrograms/100 g body wt sc) administered 1 hr or 30 min prior to the behavioral test failed to normalize disturbed exploratory activity of adrenalectomi

  10. Effect of aldosterone breakthrough on albuminuria during treatment with a direct renin inhibitor and combined effect with a mineralocorticoid receptor antagonist.

    Science.gov (United States)

    Sato, Atsuhisa; Fukuda, Seiichi

    2013-10-01

    We have reported observing aldosterone breakthrough in the course of relatively long-term treatment with renin-angiotensin (RA) system inhibitors, where the plasma aldosterone concentration (PAC) increased following an initial decrease. Aldosterone breakthrough has the potential to eliminate the organ-protective effects of RA system inhibitors. We therefore conducted a study in essential hypertensive patients to determine whether aldosterone breakthrough occurred during treatment with the direct renin inhibitor (DRI) aliskiren and to ascertain its clinical significance. The study included 40 essential hypertensive patients (18 men and 22 women) who had been treated for 12 months with aliskiren. Aliskiren significantly decreased blood pressure and plasma renin activity (PRA). The PAC was also decreased significantly at 3 and 6 months; however, the significant difference disappeared after 12 months. Aldosterone breakthrough was observed in 22 of the subjects (55%). Urinary albumin excretion differed depending on whether breakthrough occurred. For the subjects in whom aldosterone breakthrough was observed, eplerenone was added. A significant decrease in urinary albumin excretion was observed after 1 month, independent of changes in blood pressure. In conclusion, this study demonstrated that aldosterone breakthrough occurs in some patients undergoing DRI therapy. Aldosterone breakthrough affects the drug's ability to improve urinary albumin excretion, and combining a mineralocorticoid receptor antagonist with the DRI may be useful for decreasing urinary albumin excretion. When the objective is organ protection in hypertensive patients, a two-pronged approach using combination therapy to inhibit both the RA system and aldosterone may be highly effective.

  11. Advances in Aldosterone Receptor Antagonists on Hypertension%醛固酮受体拮抗剂的降压治疗进展

    Institute of Scientific and Technical Information of China (English)

    黄红娟

    2011-01-01

    The hormone aldosterone is the final product of the renin angiotensin aldosterone system, which contributes significantly to primary and sustained hypertension. Increasingly attention is being given to the role aldosterone has in influencing blood pressure. This review shows the pathophysiology of aldosterone, its classification and mechanism, and clinical uses of aldosterone receptor antagonist.%醛固酮是肾素-血管紧张素-醛固酮系统的终末环节,在原发性高血压、顽固性高血压中起重要作用.醛固酮受体拮抗剂在高血压治疗方面的作用越来越受到重视.现综述醛固酮在高血压中的病理生理作用,醛固酮受体拮抗剂的分类、降压机制及临床应用进展等.

  12. Application of aldosterone antagonists in the treatment of heart failure%醛固酮拮抗剂在心力衰竭治疗中的应用

    Institute of Scientific and Technical Information of China (English)

    高修仁; 黄至斌

    2013-01-01

    人们对醛固酮致病作用的认识已有50多年的历史,但相关指南推荐使用醛固酮拮抗剂治疗纽约心脏协会心功能分级Ⅲ~Ⅳ级、左心室射血分数≤35%的重度心力衰竭患者却仅有10年的时间。2012年,欧洲心脏病学学会发表的更新指南又将醛固酮拮抗剂治疗心力衰竭的适用人群扩展到纽约心脏协会心功能分级Ⅱ级患者。本文概要介绍醛固酮拮抗剂的作用机制、循证医学证据和注意事项等。%More than 50 years ago, scientist first observed the relationship between heart failure and aldosterone. However aldosterone antagonists were not guideline-recommended as a therapy for patients with moderate to severe heart failure till 10 years ago. In 2012 ESC guideline for aldosterone antagonists in the treatment of systolic heart failure extended to patients with mild heart failure. This review introduces the main mechanism, evidence-based medicine, clinical therapy and announcements for aldosterone antagonists in the treatment of systolic heart failure.

  13. RU28318, an Aldosterone Antagonist, in Combination with an ACE Inhibitor and Angiotensin Receptor Blocker Attenuates Cardiac Dysfunction in Diabetes

    Directory of Open Access Journals (Sweden)

    Ibrahim F. Benter

    2013-01-01

    Full Text Available Aims. We evaluated the effects of RU28318 (RU, a selective mineralocorticoid receptor (MR antagonist, Captopril (Capt, an angiotensin converting enzyme inhibitor, and Losartan (Los, an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R- induced cardiac dysfunction in hearts obtained from normal and diabetic rats. Methods. Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I followed by a period of 30 min of reperfusion (R. Drugs were administered for 30 min either before or after ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple. Recovery of cardiac hemodynamics was evaluated. Results. Recovery of cardiac function was up to 5-fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia-induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly effective as Capt or Los treatment. Conclusions. RU treatment locally might be considered as an effective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most effective at improving -dP/dt (a measure of diastolic function when administered to diabetic hearts after ischemia.

  14. Aldosterone synthase inhibitors in hypertension: current status and future possibilities

    Directory of Open Access Journals (Sweden)

    Milan Hargovan

    2014-02-01

    Full Text Available The renin-angiotensin aldosterone system is a critical mechanism for controlling blood pressure, and exerts most of its physiological effects through the action of angiotensin II. In addition to increasing blood pressure by increasing vascular resistance, angiotensin II also stimulates aldosterone secretion from the adrenal gland. Aldosterone acts to cause an increase in sodium and water reabsorption, thus elevating blood pressure. Although treatment with angiotensin converting enzyme inhibitors initially lowers circulating aldosterone, with chronic treatment aldosterone levels increase back to baseline, a phenomenon termed aldosterone escape; aldosterone blockade may therefore give added value in the treatment of hypertension. The first mineralocorticoid receptor antagonist developed was spironolactone, but its use has been severely hampered by adverse (notably oestrogenic effects. The more recently developed mineralocorticoid receptor antagonist eplerenone exhibits a better adverse effect profile, although it is not devoid of effects similar to spironolactone. In addition, aldosterone activates non-genomic receptors that are not inhibited by either eplerenone or spironolactone. It is believed that deleterious organ remodelling is mediated by aldosterone via such non-genomic pathways. A new class of drugs, the aldosterone synthase inhibitors, is currently under development. These may offer a novel therapeutic approach for both lowering blood pressure and preventing the non-genomic effects of aldosterone. Here, we will review the cardiovascular effects of aldosterone and review the drugs available that target this hormone, with a particular focus on the aldosterone synthase inhibitors.

  15. Aldosterone synthase inhibitors in hypertension: current status and future possibilities.

    Science.gov (United States)

    Hargovan, Milan; Ferro, Albert

    2014-01-01

    The renin-angiotensin aldosterone system is a critical mechanism for controlling blood pressure, and exerts most of its physiological effects through the action of angiotensin II. In addition to increasing blood pressure by increasing vascular resistance, angiotensin II also stimulates aldosterone secretion from the adrenal gland. Aldosterone acts to cause an increase in sodium and water reabsorption, thus elevating blood pressure. Although treatment with angiotensin converting enzyme inhibitors initially lowers circulating aldosterone, with chronic treatment aldosterone levels increase back to baseline, a phenomenon termed aldosterone escape; aldosterone blockade may therefore give added value in the treatment of hypertension. The first mineralocorticoid receptor antagonist developed was spironolactone, but its use has been severely hampered by adverse (notably oestrogenic) effects. The more recently developed mineralocorticoid receptor antagonist eplerenone exhibits a better adverse effect profile, although it is not devoid of effects similar to spironolactone. In addition, aldosterone activates non-genomic receptors that are not inhibited by either eplerenone or spironolactone. It is believed that deleterious organ remodelling is mediated by aldosterone via such non-genomic pathways. A new class of drugs, the aldosterone synthase inhibitors, is currently under development. These may offer a novel therapeutic approach for both lowering blood pressure and preventing the non-genomic effects of aldosterone. Here, we will review the cardiovascular effects of aldosterone and review the drugs available that target this hormone, with a particular focus on the aldosterone synthase inhibitors.

  16. The Impact Exerted on Clinical Outcomes of Patients With Chronic Heart Failure by Aldosterone Receptor Antagonists: A Meta-Analysis of Randomized Controlled Trials

    Science.gov (United States)

    De Vecchis, Renato; Cantatrione, Claudio; Mazzei, Damiana; Barone, Augusto; Maurea, Nicola

    2017-01-01

    Background Aldosterone receptor antagonists (ARAs) have been associated with improved clinical outcomes in patients with heart failure with reduced left ventricular ejection fraction (HFREF), but not in those with heart failure with preserved left ventricular ejection fraction (HFpEF). With the aim to study this topic more deeply, we carried out a meta-analysis of selective and non-selective ARAs in HFREF and HFpEF. Methods We searched PubMed and Scopus databases. We decided to incorporate in the meta-analysis only randomized controlled trials (RCTs) of ARAs in patients with chronic heart failure (CHF) if they met the following criteria: experimental groups included patients with CHF treated with ARAs in addition to the conventional therapy; control groups included patients with CHF receiving conventional therapy without ARAs. Outcomes of interest were all-cause death, hospitalizations from cardiovascular cause, hyperkalemia, or gynecomastia. Results We detected 15 studies representing 15,671 patients. ARAs were associated with a reduced odds of all-cause death (odds ratio (OR): 0.79; 95% confidence interval (CI): 0.73 - 0.87) and hospitalizations from cardiovascular cause (OR: 0.73; 95% CI: 0.61 - 0.89). However, subgroup analysis showed that these advantages were limited to HFREF (all-cause death: OR: 0.77, 95% CI: 0.69 - 0.84; hospitalizations from cardiovascular cause: OR: 0.66, 95% CI: 0.51 - 0.85), but they did not affect the HFpEF group (all-cause death: OR: 0.91, 95% CI: 0.76 - 1.1; hospitalizations from cardiovascular cause: OR: 0.85, 95% CI: 0.7 - 1.09). ARAs increased the risk of hyperkalemia (OR: 2.17; 95% CI: 1.88 - 2.5). Non-selective ARAs, but not selective ARAs, increased the risk of gynecomastia (OR: 8.22, 95% CI: 4.9 - 13.81 vs. OR: 0.74, 95% CI: 0.43 - 1.27). Conclusions ARAs reduced the risk of adverse cardiac events in HFREF but not HFpEF. In particular, ARA use in HFpEF patients is questionable, since in this CHF type, no significant

  17. Safety of Aldosterone Receptor Antagonists in Heart Failure%醛固酮受体拮抗剂在心力衰竭患者中应用的安全性

    Institute of Scientific and Technical Information of China (English)

    戴士鹏(综述); 徐泽升(审校)

    2015-01-01

    Although the benefits of aldosterone receptor antagonists have been confirmed with multiple randomized,controlled studies and recommended by heart failure guideline,only a fraction of the patients with heart failure who are eligible for the indications receive this medication .This maybe, in part, concerns of adverse events-hyperkalemia and deteriorated renal function known to occur with using of these drugs.Here is to make a review of the safety of aldosterone receptor antagonists in heart failure , in order to improve the knowledge of this kind of drugs.%尽管应用醛固酮受体拮抗剂治疗心力衰竭的益处被多个大型临床随机对照试验所证实,并被临床治疗指南所推荐,但仅有一小部分适合应用醛固酮受体拮抗剂治疗的心力衰竭患者应用了这一药物,其部分原因是临床医师对醛固酮受体拮抗剂的主要不良反应———高钾血症和肾功能恶化的担心。该文对醛固酮受体拮抗剂在心力衰竭患者中应用的安全性做一综述,以提高人们对于这类药物的认识。

  18. Long-term treatment with an aldosterone synthase inhibitor improves cardiac function and myocardial structure in rats with chronic heart failure

    Institute of Scientific and Technical Information of China (English)

    VirginieMELLIN; PaulMULDER; BenoitDiMEGLIO; JeanPaulHENRY; ChristianTHUILLEZ

    2004-01-01

    AIM: Aldosterone receptor antagonists reduce total and cardiovascular mortality in patients with chronic heart failure (CHF) under active angiotensin converting enzyme inhibition treatment,illustrating the deleterious involvement of aldosterone in the progression of CHF. The reduction of aldosterone synthesis through inhibition of aldosterone synthase is an alternative way to prevent the effects of aldosterone. However, whether chronic aldosterone synthase inhibition exerts beneficial effects in CHF

  19. Aldosterone and vascular damage.

    Science.gov (United States)

    Duprez, D; De Buyzere, M; Rietzschel, E R; Clement, D L

    2000-06-01

    Although the aldosterone escape mechanism is well known, aldosterone has often been neglected in the pathophysiologic consequences of the activated renin-angiotensin-aldosterone system in arterial hypertension and chronic heart failure. There is now evidence for vascular synthesis of aldosterone aside from its secretion by the adrenal cortex. Moreover, aldosterone is involved in vascular smooth muscle cell hypertrophy and hyperplasia, as well as in vascular matrix impairment and endothelial dysfunction. The mechanisms of action of aldosterone may be either delayed (genomic) or rapid (nongenomic). Deleterious effects of aldosterone leading to vascular target-organ damage include (besides salt and water retention) decreased arterial and venous compliance, increased peripheral vascular resistance, and impaired autonomic vascular control due to baroreflex dysfunction.

  20. Beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine, diuretics, aldosterone antagonist, ivabradine, devices and digoxin (BANDAID(2) ): an evidence-based mnemonic for the treatment of systolic heart failure.

    Science.gov (United States)

    Chia, N; Fulcher, J; Keech, A

    2016-06-01

    Heart failure causes significant morbidity and mortality, with recognised underutilisation rates of guideline-based therapies. Our aim was to review current evidence for heart failure treatments and derive a mnemonic summarising best practice, which might assist physicians in patient care. Treatments were identified for review from multinational society guidelines and recent randomised trials, with a primary aim of examining their effects in systolic heart failure patients on mortality, hospitalisation rates and symptoms. Secondary aims were to consider other clinical benefits. MEDLINE and EMBASE were searched using a structured keyword strategy and the retrieved articles were evaluated methodically to produce an optimised reference list for each treatment. We devised the mnemonic BANDAID (2) , standing for beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine (or potentially neprilysin inhibitor), diuretics, aldosterone antagonist, ivabradine, devices (automatic implantable cardioverter defibrillator, cardiac resynchronisation therapy or both) and digoxin as a representation of treatments with strong evidence for their use in systolic heart failure. Treatment with omega-3 fatty acids, statins or anti-thrombotic therapies has limited benefits in a general heart failure population. Adoption of this mnemonic for current evidence-based treatments for heart failure may help improve prescribing rates and patient outcomes in this debilitating, high mortality condition.

  1. The regulation of cell growth and survival by aldosterone.

    LENUS (Irish Health Repository)

    Dooley, Ruth

    2011-01-01

    The steroid hormone aldosterone is synthesized from cholesterol, mainly in the zona glomerulosa of the adrenal cortex. Aldosterone exerts its effects in the epithelial tissues of the kidney and colon and in non-epithelial tissues such as the brain and cardiovasculature. The genomic response to aldosterone involves dimerization of the mineralocorticoid receptor (MR), dissociation of heat shock proteins from MR, translocation of the aldosterone-MR complex to the nucleus and the concomitant regulation of gene expression. Rapid responses to aldosterone occur within seconds to minutes, do not involve transcription or translation and can modulate directly or indirectly the later genomic responses. Aside from the well-known effects of aldosterone on the regulation of sodium and water homeostasis, aldosterone can also produce deleterious structural changes in tissues by inducing hypertrophy and the dysregulation of proliferation and apoptosis, leading to fibrosis and tissue remodelling. Here we discuss the involvement of aldosterone-mediated rapid signalling cascades in the development of disease states such as chronic kidney disease and heart failure, and the antagonists that can inhibit these pathophysiological responses.

  2. The regulation of cell growth and survival by aldosterone.

    LENUS (Irish Health Repository)

    Dooley, Ruth

    2012-02-01

    The steroid hormone aldosterone is synthesized from cholesterol, mainly in the zona glomerulosa of the adrenal cortex. Aldosterone exerts its effects in the epithelial tissues of the kidney and colon and in non-epithelial tissues such as the brain and cardiovasculature. The genomic response to aldosterone involves dimerization of the mineralocorticoid receptor (MR), dissociation of heat shock proteins from MR, translocation of the aldosterone-MR complex to the nucleus and the concomitant regulation of gene expression. Rapid responses to aldosterone occur within seconds to minutes, do not involve transcription or translation and can modulate directly or indirectly the later genomic responses. Aside from the well-known effects of aldosterone on the regulation of sodium and water homeostasis, aldosterone can also produce deleterious structural changes in tissues by inducing hypertrophy and the dysregulation of proliferation and apoptosis, leading to fibrosis and tissue remodelling. Here we discuss the involvement of aldosterone-mediated rapid signalling cascades in the development of disease states such as chronic kidney disease and heart failure, and the antagonists that can inhibit these pathophysiological responses.

  3. Aldosterone does not predict cardiovascular events following acute coronary syndrome in patients initially without heart failure

    OpenAIRE

    Pitts, Reynaria; Gunzburger, Elise; Ballantyne, Christie M.; Barter, Philip J.; Kallend, David; Leiter, Lawrence A.; Leitersdorf, Eran; Nicholls, Stephen J.; Prediman K Shah; Tardif, Jean-Claude; Olsson, Anders G.; McMurray, John J.V.; Kittelson, John; Schwartz, Gregory G.

    2017-01-01

    Background: Aldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldosterone antagonist reduces cardiovascular risk in patients with acute myocardial infarction complicated by heart failure (HF) and left ventricular systolic dysfunction. However, most patients with acute coronary syndrome do not have advanced HF. Among such patients, it is unknown whether aldosterone predicts cardiovascular risk.\\ud \\ud Methods and Results: To address this question, we exa...

  4. Histamine-dependent prolongation by aldosterone of vasoconstriction in isolated small mesenteric arteries of the mouse

    DEFF Research Database (Denmark)

    Schjerning, Jeppe; Uhrenholt, Torben R; Svenningsen, Per;

    2013-01-01

    In arterioles, aldosterone counteracts the rapid dilatation ("recovery") following depolarization-induced contraction. The hypothesis was tested that this effect of aldosterone depends on COX-derived products and/or NOS inhibition. Recovery of the response to high K(+) was observed in mesenteric...... arteries of wild type and COX-2(-/-) mice but it was significantly diminished in preparations from eNOS(-/-) mice. Aldosterone pretreatment inhibited recovery from wild type and COX-2(-/-) mice. The NO-donor sodium nitroprusside (SNP) restored recovery in arteries from eNOS(-/-) mice and this was inhibited...... by aldosterone. Actinomycin-D abolished the effect of aldosterone indicating a genomic effect. The effect was blocked by indomethacin and by the COX-1 inhibitor valeryl salicylate but not by NS-398 (10(-6) mol/L) or the TP-receptor antagonist S18886 (10(-7) mol/L). The effect of aldosterone on recovery...

  5. Moderate antiproteinuric effect of add-on aldosterone blockade with eplerenone in non-diabetic chronic kidney disease. A randomized cross-over study

    DEFF Research Database (Denmark)

    Boesby, Lene; Elung-Jensen, Thomas; Klausen, Tobias Wirenfeldt;

    2011-01-01

    Reduction of proteinuria and blood pressure (BP) with blockers of the renin-angiotensin system (RAS) impairs the progression of chronic kidney disease (CKD). The aldosterone antagonist spironolactone has an antiproteinuric effect, but its use is limited by side effects. The present study evaluated...... the short-term antiproteinuric effect and safety of the selective aldosterone antagonist eplerenone in non-diabetic CKD....

  6. Aldosterone and Its Blockade: A Cardiovascular and Renal Perspective

    Directory of Open Access Journals (Sweden)

    V. Lahera

    2006-01-01

    Full Text Available Aldosterone not only contributes to salt and water homeostasis, but also exerts direct cardiovascular and renal effects. Numerous experimental and clinical studies indicate that aldosterone participate in cardiac alterations associated with hypertension, heart failure, diabetes and other pathological entities. It is important to mention that dietary salt is a key factor in aldosterone-mediated cardiovascular damage, since damage was moreevident in animals on a high-salt diet than animals on a low salt diet. A pathophysiological action of aldosterone involves development of extracellular matrix and fibrosis, inflammation, stimulation of reactive oxygen species production, endothelial dysfunction, cell growth and proliferation. Many studies showed local extra-adrenal production of aldosterone in brain blood vessel, and the heart, which contribute in an important manner to the pathological actions of this mineralocorticoid.Several studies such as RALES, EPHESUS, 4E and others, recently showed that mineralocorticoid-receptor (MR antagonists, alone or in combination with ACE inhibitors or ARBs, reduced the risk of progressive target organ damage and hospitalization in patients with hypertension and heart failure. These clinical benefits support the therapeutic usefulness of MR antagonists.

  7. Aldosterone and volume management in hypertensive heart disease.

    Science.gov (United States)

    Sica, Domenic A

    2014-05-01

    Aldosterone-receptor antagonists dose-dependently reduce both the epithelial and nonepithelial actions of aldosterone. These compounds are used commonly in the treatment of hypertension, with or without aldosteronism, and in the volume-overload periods of various forms of heart failure, cirrhosis, and renal failure. In this regard, the relevant site of action for these compounds is compartmentalized to the distal nephron. The cardiac benefits of aldosterone-receptor blockade now are sufficiently well established to warrant routine use of these compounds for their survival benefits in moderate to advanced stages of heart failure. Aldosterone-receptor antagonists spironolactone and eplerenone commonly are used in the treatment of resistant forms of hypertension. Spironolactone, but not eplerenone, is a commonly used add-on diuretic that provides incremental benefit for salt-and-water excretion in excess of what may be seen with a loop diuretic given together with a thiazide-type diuretic. The dose-response relationship for natriuresis with spironolactone has not been explored completely as to its combination therapy responses. The quite high doses of spironolactone used in patients with cirrhosis and ascites would infer that the overall treatment effect with this compound exceeds simple receptor blockade and may include a nervous system effect that operationally reduces renal sympathetic nerve traffic. The adverse electrolyte and renal function side effects with aldosterone-receptor antagonists are not uncommon in at-risk patients, such as those with chronic kidney disease, and require that dosing be mindful of the tendency of these drugs to importantly increase serum potassium levels.

  8. Factors affecting the aldosterone/renin ratio.

    Science.gov (United States)

    Stowasser, M; Ahmed, A H; Pimenta, E; Taylor, P J; Gordon, R D

    2012-03-01

    Although the aldosterone/renin ratio (ARR) is the most reliable screening test for primary aldo-steronism, false positives and negatives occur. Dietary salt restriction, concomitant malignant or renovascular hypertension, pregnancy and treatment with diuretics (including spironolactone), dihydropyridine calcium blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor antagonists can produce false negatives by stimulating renin. We recently reported selective serotonin reuptake inhibitors lower the ratio. Because potassium regulates aldosterone, uncorrected hypokalemia can lead to false negatives. Beta-blockers, alpha-methyldopa, clonidine, and nonsteroidal anti-inflammatory drugs suppress renin, raising the ARR with potential for false positives. False positives may occur in patients with renal dysfunction or advancing age. We recently showed that (1) females have higher ratios than males, and (2) false positive ratios can occur during the luteal menstrual phase and while taking an oral ethynylestradiol/drospirenone (but not implanted subdermal etonogestrel) contraceptive, but only if calculated using direct renin concentration and not plasma renin activity. Where feasible, diuretics should be ceased at least 6 weeks and other interfering medications at least 2 before ARR measurement, substituting noninterfering agents (e. g., verapamil slow-release±hydralazine and prazosin or doxazosin) were required. Hypokalemia should be corrected and a liberal salt diet encouraged. Collecting blood midmorning from seated patients following 2-4 h upright posture improves sensitivity. The ARR is a screening test only and should be repeated once or more before deciding whether to proceed to confirmatory suppression testing. Liquid chromatography-tandem mass spectrometry aldosterone assays represent a major advance towards addressing inaccuracies inherent in other available methods.

  9. Aldosterone aggravates glucose intolerance induced by high fructose.

    Science.gov (United States)

    Sherajee, Shamshad J; Rafiq, Kazi; Nakano, Daisuke; Mori, Hirohito; Kobara, Hideki; Hitomi, Hirofumi; Fujisawa, Yoshihide; Kobori, Hiroyuki; Masaki, Tsutomu; Nishiyama, Akira

    2013-11-15

    We previously reported that aldosterone impaired vascular insulin signaling in vivo and in vitro. Fructose-enriched diet induces metabolic syndrome including hypertension, insulin resistance, hyperlipidemia and diabetes in animal. In the current study, we hypothesized that aldosterone aggravated fructose feeding-induced glucose intolerance in vivo. Rats were divided into five groups for six-week treatment; uninephrectomy (Unx, n=8), Unx+aldosterone (aldo, 0.75 µg/h, s.c., n=8), Unx+fructose (fruc, 10% in drinking water, n=8), Unx+aldo+fruc, (aldo+fruc, n=8), and Unx+aldo+fruc+spironolactone, a mineralocorticoid receptor antagonist (aldo+fruc+spiro, 20mg/kg/day, p.o., n=8). Aldo+fruc rats manifested the hypertension, and induced glucose intolerance compared to fruc intake rats assessed by oral glucose tolerance test, homeostasis model assessment of insulin resistance and hyperinsulinemic-euglycemic clamp study. Spironolactone, significantly improved the aldosterone-accelerated glucose intolerance. Along with improvement in insulin resistance, spironolactone suppressed upregulated mineralocorticoid receptor (MR) target gene, serum and glucocorticoid-regulated kinases-1 mRNA expression in skeletal muscle in aldo+fruc rats. In conclusion, these data suggested that aldosterone aggravates fructose feeding-induced glucose intolerance through MR activation.

  10. Aldosterone-induced brain MAPK signaling and sympathetic excitation are angiotensin II type-1 receptor dependent.

    Science.gov (United States)

    Zhang, Zhi-Hua; Yu, Yang; Wei, Shun-Guang; Felder, Robert B

    2012-02-01

    Angiotensin II (ANG II)-induced mitogen-activated protein kinase (MAPK) signaling upregulates angiotensin II type-1 receptors (AT(1)R) in hypothalamic paraventricular nucleus (PVN) and contributes to AT(1)R-mediated sympathetic excitation in heart failure. Aldosterone has similar effects to increase AT(1)R expression in the PVN and sympathetic drive. The present study was undertaken to determine whether aldosterone also activates the sympathetic nervous system via MAPK signaling and, if so, whether its effect is independent of ANG II and AT(1)R. In anesthetized rats, a 4-h intravenous infusion of aldosterone induced increases (P < 0.05) in phosphorylated (p-) p44/42 MAPK in PVN, PVN neuronal excitation, renal sympathetic nerve activity (RSNA), mean blood pressure (MBP), and heart rate (HR). Intracerebroventricular or bilateral PVN microinjection of the p44/42 MAPK inhibitor PD-98059 reduced the aldosterone-induced RSNA, HR, and MBP responses. Intracerebroventricular pretreatment (5 days earlier) with pooled small interfering RNAs targeting p44/42 MAPK reduced total and p-p44/42 MAPK, aldosterone-induced c-Fos expression in the PVN, and the aldosterone-induced increases in RSNA, HR, and MBP. Intracerebroventricular infusion of either the mineralocorticoid receptor antagonist RU-28318 or the AT(1)R antagonist losartan blocked aldosterone-induced phosphorylation of p44/42 MAPK and prevented the increases in RSNA, HR, and MBP. These data suggest that aldosterone-induced sympathetic excitation depends upon that AT(1)R-induced MAPK signaling in the brain. The short time course of this interaction suggests a nongenomic mechanism, perhaps via an aldosterone-induced transactivation of the AT(1)R as described in peripheral tissues.

  11. A SELECTIVE ANTAGONIST OF MINERALOCORTICOID RECEPTOR EPLERENONE IN CARDIOLOGY PRACTICE

    Directory of Open Access Journals (Sweden)

    B. B. Gegenava

    2015-09-01

    Full Text Available The role of aldosterone in pathophysiological processes is considered. The effects of the selective antagonist of mineralocorticoid receptor eplerenone are analyzed. The advantages of eplerenone compared with spironolactone are discussed.

  12. The Effect of Dopaminergic Activity on Aldosterone Secretion in Edematous State

    Energy Technology Data Exchange (ETDEWEB)

    Han, Bong Heon; Ro, Heung Kyu [Chungnam National University College of Medicine, Daejeon (Korea, Republic of)

    1985-09-15

    To evaluate the effect of dopaminergic activity on aldosterone secretion, the plasma renin activity, serum cortisol and aldosterone were measured by radioimmunoassay in 6 normal controls and 12 patients who had hyponatremia and generalized edema or ascites with possible condition with secondary aldosteronism before and after(15, 30, and 60 min) 15 mg of metaclopramide by iv bolus injection and same method with 500 mg of L-dopa by per oral in 6 normal controls and 12 patients with edema ascites. The result were as follows; l) The basal level of PRA was higher in patients rather than normal controls but PRA was not influenced by MC or L-dopa administration on both normal controls and patients group. 2) The serum cortisol level was significantly elevated at 30 min after MC injection compared with basal level in normal controls but no significant change was not patients group. After L-dopa administration the serum cortisol level was noted in changed in both normal controls and patients group, 3) The serum aldosterone level was significantly elevated in 15, 30 and 60 min after MC injection in normal controls, and there also same tendency of aldosterone secretion was noticed in patients group. On the other hands, there was no changes in aldosterone level in both normal controls and patients group with L-dopa administration. Above result means that MC stimulate aldosterone secretion by dopaminergic antagonist and aldosterone secretion in normal subject is controlled by maximal tonic dopaminergic inhibition. In edematous patients, however, both of the dopaminergic inhibitory and stimulating effect of PRA, ACTH etc on the aldosterone secretion seems to be variable.

  13. [Hypertension in the course of primary aldosteronism during pregnancy].

    Science.gov (United States)

    Wyskida, Magdalena; Wyskida, Katarzyna; Olszanecka-Glinianowicz, Magdalena; Maruniak-Chudek, Iwona; Sikora, Jerzy; Chudek, Jerzy

    2015-02-15

    Hypertension is one of the most common cardiovascular diseases during pregnancy. Primary hyperaldosteronism (PHA) is the most frequent endocrinological, secondary cause of hypertension, rarely diagnosed in pregnant women. In the available literature about 50 cases of PHA in pregnant women have been described. PHA is often a cause of resistant hypertension. PHA can cause life-threatening complications both for the pregnant woman and the fetus. Diagnosis of PHA in pregnancy is difficult due to the antagonistic effect of progesterone on aldosterone, physiological increase of aldosterone release during gestation and frequent normokalaemic clinical course. Typical pharmacological treatment of PHA is limited due to the anti‑androgenic effect of spironolactone, lack of data concerning the safety of eplerenone and limited access to amiloride in Poland. Surgical treatment is a therapeutic option only in early pregnancy. This paper presents the current state of knowledge on diagnostic methods and treatment of PHA in pregnant women and a systematic review of cases described in the literature.

  14. Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes

    Energy Technology Data Exchange (ETDEWEB)

    Queisser, Nina; Happ, Kathrin; Link, Samuel [Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg (Germany); Jahn, Daniel [Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg (Germany); Zimnol, Anna [Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg (Germany); Geier, Andreas [Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg (Germany); Schupp, Nicole, E-mail: schupp@uni-duesseldorf.de [Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg (Germany)

    2014-11-01

    Mineralocorticoid receptor blockers show antifibrotic potential in hepatic fibrosis. The mechanism of this protective effect is not known yet, although reactive oxygen species seem to play an important role. Here, we investigated the effects of elevated levels of aldosterone (Ald), the primary ligand of the mineralocorticoid receptor, on livers of rats in a hyperaldosteronism model: aldosterone-induced hypertension. Male Sprague–Dawley rats were treated for 4 weeks with aldosterone. To distinguish if damage caused in the liver depended on increased blood pressure or on increased Ald levels, the mineralocorticoid receptor antagonist spironolactone was given in a subtherapeutic dose, not normalizing blood pressure. To investigate the impact of oxidative stress, the antioxidant tempol was administered. Aldosterone induced fibrosis, detected histopathologically, and by expression analysis of the fibrosis marker, α-smooth muscle actin. Further, the mRNA amount of the profibrotic cytokine TGF-β was increased significantly. Fibrosis could be reduced by scavenging reactive oxygen species, and also by blocking the mineralocorticoid receptor. Furthermore, aldosterone treatment caused oxidative stress and DNA double strand breaks in livers, as well as the elevation of DNA repair activity. An increase of the transcription factor Nrf2, the main regulator of the antioxidative response could be observed, and of its target genes heme oxygenase-1 and γ-glutamylcysteine synthetase. All these effects of aldosterone were prevented by spironolactone and tempol. Already after 4 weeks of treatment, aldosteroneinfusion induced fibrosis in the liver. This effect was independent of elevated blood pressure. DNA damage caused by aldosterone might contribute to fibrosis progression when aldosterone is chronically increased. - Highlights: • Aldosterone has direct profibrotic effects on the liver independent of blood pressure. • Fibrosis is mediated by the mineralocorticoid receptor and

  15. Why are mineralocorticoid receptor antagonists cardioprotective?

    NARCIS (Netherlands)

    W. Chai (Wenxia); A.H.J. Danser (Jan)

    2006-01-01

    textabstractTwo clinical trials, the Randomized ALdosterone Evaluation Study (RALES) and the EPlerenone HEart failure and SUrvival Study (EPHESUS), have recently shown that mineralocorticoid receptor (MR) antagonists reduce mortality in patients with heart failure on top of ACE inhibition. This effe

  16. Aldosterone as a renal growth factor.

    LENUS (Irish Health Repository)

    Thomas, Warren

    2011-04-05

    Aldosterone regulates blood pressure through its effects on the cardiovascular system and kidney. Aldosterone can also contribute to the development of hypertension that leads to chronic pathologies such as nephropathy and renal fibrosis. Aldosterone directly modulates renal cell proliferation and differentiation as part of normal kidney development. The stimulation of rapidly activated protein kinase cascades is one facet of how aldosterone regulates renal cell growth. These cascades may also contribute to myofibroblastic transformation and cell proliferation observed in pathological conditions of the kidney. Polycystic kidney disease is a genetic disorder that is accelerated by hypertension. EGFR-dependent proliferation of the renal epithelium is a factor in cyst development and trans-activation of EGFR is a key feature in initiating aldosterone-induced signalling cascades. Delineating the components of aldosterone-induced signalling cascades may identify novel therapeutic targets for proliferative diseases of the kidney.

  17. Targeting the aldosterone pathway in cardiovascular disease

    DEFF Research Database (Denmark)

    Gustafsson, Finn; Azizi, Michel; Bauersachs, Johann

    2012-01-01

    Accumulated evidence has demonstrated that aldosterone is a key player in the pathogenesis of cardiovascular (CV) disease. Multiple clinical trials have documented that intervention in the aldosterone pathway can reduce blood pressure and lower albuminuria and improve outcome in patients with heart...... failure or myocardial infarction. Recent studies have unraveled details about the role of aldosterone at the cellular level in CV disease. The relative importance of glucocorticoids and aldosterone in terms of mineralocorticoid receptor activation is currently being debated. Also, studies are addressing...... which aldosterone modulator to use, which timing of treatment to aim for, and in which population to intervene. This review provides an overview of recent developments in the understanding of the role of aldosterone in CV disease, with particular reference to mechanisms and potential targets...

  18. This Is Not Dr. Conn's Aldosterone Anymore

    OpenAIRE

    Brown, Nancy J.

    2011-01-01

    In 1955, Dr. Jerome Conn described a patient with severe hypertension and hypokalemia and an aldosterone-secreting adenoma. The prevalence of hyperaldosteronism is increased among patients with obesity or resistant hypertension. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers reduce the secretion of aldosterone, but with chronic treatment aldosterone concentrations “escape” back to baseline values. Mineralocorticoid receptor (MR) antagonism reduces mortality i...

  19. Pleiotropic action of aldosterone in epithelia mediated by transcription and post-transcription mechanisms.

    Science.gov (United States)

    Verrey, F; Pearce, D; Pfeiffer, R; Spindler, B; Mastroberardino, L; Summa, V; Zecevic, M

    2000-04-01

    The aldosterone-induced increase in sodium reabsorption across tight epithelia can be divided schematically into two functional phases: an early regulatory phase starting after a lag period of 20 to 60 minutes, during which the pre-existing transport machinery is activated, and a late phase (>2.5 h), which can be viewed as an anabolic action leading to a further amplification/differentiation of the Na+ transport machinery. At the transcriptional level, both early and late responses are initiated during the lag period, but the functional impact of newly synthesized regulatory proteins is faster than that of the structural ones. K-Ras2 and SGK were identified as the first early aldosterone-induced regulatory proteins in A6 epithelia. Their mRNAs also were shown to be regulated in vivo by aldosterone, and their expression (constitutively active K-Ras2 and wild-type SGK) was shown to increase the function of ENaC coexpressed in Xenopus oocytes. Recently, aldosterone was also shown to act on transcription factors in A6 epithelia: It down-regulates the mRNAs of the proliferation-promoting c-Myc, c-Jun, and c-Fos by a post-transcriptional mechanism, whereas it up-regulates that of Fra-2 (c-Fos antagonist) at the transcriptional level. Together, these new data illustrate the complexity of the regulatory network controlled by aldosterone and support the view that its early action is mediated by the induction of key regulatory proteins such as K-Ras2 and SGK. These early induced proteins are sites of convergence for different regulatory inputs, and thus, their aldosterone-regulated expression level tunes the impact of other regulatory cascades on sodium transport. This suggests mechanisms for the escape from aldosterone action.

  20. 黄芪多糖、丹参酮联合醛固酮受体拮抗剂对 CHF 模型大鼠 MIF、TNF-α、IL-6 的影响%Effect of astragalus polysaccharides, tanshinone combined with aldosterone receptor antagonist on MIF, TNF-ɑ and IL-6 in chronic heart failure model rats

    Institute of Scientific and Technical Information of China (English)

    肖大刚

    2015-01-01

    Objective It is to study the effects of astragalus polysaccharide, tanshinone combined with aldosterone receptor antagonist on macrophage migration inhibitory factor ( MIF) , TNF-αand IL-6 in chronic heart failure ( CHF) model rats. Methods 60 male SD rats were randomly divided into six groups: control group, model group, astragalus polysaccharides+tanshinone group, spironolactone group, astragalus polysaccharides+tanshinone +spironolactone group and atorvastatin group each group had 10 rats.All the rats except that in control group were given adriamycin by intraperitoneal injection to establish CHF models.After successfully establishing, every treatment group was given respective medicine by intragastric administra-tion, control group and model group was given normal saline.The symptoms and signs of the rats during establishing and treat-ment were observed, body weight was measured, LVWI were detected by echocardiography, the levels of serum MIF, TNF-αand IL-6 were determined by ELISA.Results Compared with control group, the rats in model group showed CHF symp-toms such as listlessness, little activity, loss of appetite, echocardiography showed left ventricular end-diastolic diameter ( LVEDD) , left ventricular systolic diameter ( LVESD) increased significantly, left ventricular ejection fraction ( LVEF) and left ventricular short axis shortening rate (LVFS) significantly decreased;Left ventricular mass index (LVWI) and right ven-tricular mass index ( RVWI) increased significantly;the levels of serum MIF, TNF-αand IL-6 increased obviously.In ev-ery treatment group, CHF symptoms improved obviously; LVEDD, LVESD decrease obviously, LVFS and LVEF increased significantly;the levels of serum MIF, TNF-αand IL-6 decreased obviously, and the improvements were the best in astrag-alus polysaccharides+tanshinone+spironolactone group.Conclusion Astragalus polysaccharides, tanshinone combined with aldosterone receptor antagonist can down-regulate the levels of serum MIF

  1. Serum aldosterone and death, end-stage renal disease, and cardiovascular events in blacks and whites: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

    Science.gov (United States)

    Deo, Rajat; Yang, Wei; Khan, Abigail M; Bansal, Nisha; Zhang, Xiaoming; Leonard, Mary B; Keane, Martin G; Soliman, Elsayed Z; Steigerwalt, Susan; Townsend, Raymond R; Shlipak, Michael G; Feldman, Harold I

    2014-07-01

    Prior studies have demonstrated that elevated aldosterone concentrations are an independent risk factor for death in patients with cardiovascular disease. Limited studies, however, have evaluated systematically the association between serum aldosterone and adverse events in the setting of chronic kidney disease. We investigated the association between serum aldosterone and death and end-stage renal disease in 3866 participants from the Chronic Renal Insufficiency Cohort. We also evaluated the association between aldosterone and incident congestive heart failure and atherosclerotic events in participants without baseline cardiovascular disease. Cox proportional hazards models were used to evaluate independent associations between elevated aldosterone concentrations and each outcome. Interactions were hypothesized and explored between aldosterone and sex, race, and the use of loop diuretics and renin-angiotensin-aldosterone system inhibitors. During a median follow-up period of 5.4 years, 587 participants died, 743 developed end-stage renal disease, 187 developed congestive heart failure, and 177 experienced an atherosclerotic event. Aldosterone concentrations (per SD of the log-transformed aldosterone) were not an independent risk factor for death (adjusted hazard ratio, 1.00; 95% confidence interval, 0.93-1.12), end-stage renal disease (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99-1.17), or atherosclerotic events (adjusted hazard ratio, 1.04; 95% confidence interval, 0.85-1.18). Aldosterone was associated with congestive heart failure (adjusted hazard ratio, 1.21; 95% confidence interval, 1.02-1.35). Among participants with chronic kidney disease, higher aldosterone concentrations were independently associated with the development of congestive heart failure but not for death, end-stage renal disease, or atherosclerotic events. Further studies should evaluate whether mineralocorticoid receptor antagonists may reduce adverse events in individuals with

  2. Protein kinase D stabilizes aldosterone-induced ERK1/2 MAP kinase activation in M1 renal cortical collecting duct cells to promote cell proliferation.

    LENUS (Irish Health Repository)

    McEneaney, Victoria

    2010-01-01

    Aldosterone elicits transcriptional responses in target tissues and also rapidly stimulates the activation of protein kinase signalling cascades independently of de novo protein synthesis. Here we investigated aldosterone-induced cell proliferation and extra-cellular regulated kinase 1 and 2 (ERK1\\/2) mitogen activated protein (MAP) kinase signalling in the M1 cortical collecting duct cell line (M1-CCD). Aldosterone promoted the proliferative growth of M1-CCD cells, an effect that was protein kinase D1 (PKD1), PKCdelta and ERK1\\/2-dependent. Aldosterone induced the rapid activation of ERK1\\/2 with peaks of activation at 2 and 10 to 30 min after hormone treatment followed by sustained activation lasting beyond 120 min. M1-CCD cells suppressed in PKD1 expression exhibited only the early, transient peaks in ERK1\\/2 activation without the sustained phase. Aldosterone stimulated the physical association of PKD1 with ERK1\\/2 within 2 min of treatment. The mineralocorticoid receptor (MR) antagonist RU28318 inhibited the early and late phases of aldosterone-induced ERK1\\/2 activation, and also aldosterone-induced proliferative cell growth. Aldosterone induced the sub-cellular redistribution of ERK1\\/2 to the nuclei at 2 min and to cytoplasmic sites, proximal to the nuclei after 30 min. This sub-cellular distribution of ERK1\\/2 was inhibited in cells suppressed in the expression of PKD1.

  3. Aldosterone stimulates nuclear factor-kappa B activity and transcription of intercellular adhesion molecule-1 and connective tissue growth factor in rat mesangial cells via serum- and glucocorticoid-inducible protein kinase-1.

    Science.gov (United States)

    Terada, Yoshio; Ueda, Satoko; Hamada, Kazu; Shimamura, Yoshiko; Ogata, Koji; Inoue, Kosuke; Taniguchi, Yoshinori; Kagawa, Toru; Horino, Taro; Takao, Toshihiro

    2012-02-01

    Several clinical and experimental data support the hypothesis that aldosterone contributes to the progression of renal injury. To determine the signaling pathway of aldosterone in relation to fibrosis and inflammation in mesangial cells, we investigated the effects of aldosterone on expression and activation of serum- and glucocorticoid-inducible protein kinase-1 (SGK1), the activation of nuclear factor-kappa B (NF-κB activation, and the expressions of intercellular adhesion molecule-1 (ICAM-1) and connective tissue growth factor (CTGF). Aldosterone stimulated SGK1 expression, phosphorylation (Ser-256), and kinase activity. The increments of phosphorylation and expression of SGK1 induced by aldosterone were inhibited by mineralocorticoid receptor (MR) inhibitor (eplerenone). Aldosterone stimulated NF-κB activity measured by NF-κB responsive elements, luciferase assay, and the levels of inhibitor of kappa B (IκB) phosphorylation. This aldosterone-induced activation of NF-κB was inhibited by the transfection of dominant-negative SGK1. Furthermore, aldosterone augmented the promoter activities and protein expressions of ICAM-1 and CTGF. The effects of aldosterone on ICAM-1 and CTGF promoter activities and protein expressions were inhibited by the transfection of dominant-negative SGK1 and dominant-negative IκBα. We also found that the MR antagonist significantly ameliorated the glomerular injury and enhancements in SGK1, ICAM-1, and CTGF expressions induced by 1% sodium chloride and aldosterone in vivo. In conclusion, our findings suggest that aldosterone stimulates ICAM-1 and CTGF transcription via activation of SGK1 and NF-κB, which may be involved in the progression of aldosterone-induced mesangial fibrosis and inflammation. MR antagonists may serve as useful therapeutic targets for the treatment of glomerular inflammatory disease.

  4. Effects of aldosterone on intralymphocytic sodium and potassium in patients with primary aldosteronism.

    Science.gov (United States)

    Wehling, M; Kuhls, S; Witzgall, H; Kuhnle, U; Armanini, D; Theisen, K

    1987-12-01

    In vitro effects of aldosterone have been described with regard to the intracellular sodium and potassium concentrations of human mononuclear leukocytes. In the present paper the in vitro effect of aldosterone on the intracellular sodium and potassium of human mononuclear leukocytes in 6 patients with primary aldosteronism was investigated. Except for one patient with elevated intracellular electrolytes, sodium and potassium in mononuclear leukocytes of patients with aldosteronism without incubation were within the range for normals. In the patients, no significant change of intracellular sodium or potassium was observed during incubation with or without aldosterone (1.4 nmol/l), whereas in normals, the loss of sodium and potassium during incubation without aldosterone was prevented by 1.4 nmol/l aldosterone. This insensitivity to aldosterone indicates that intracellular electrolytes in mononuclear leukocytes of patients with primary aldosteronism are kept in normal ranges by mechanism which are independent of mineralocorticoids and may represent the cellular correlate to the renal 'escape' phenomenon in aldosteronism.

  5. This is not Dr. Conn's aldosterone anymore.

    Science.gov (United States)

    Brown, Nancy J

    2011-01-01

    In 1955, Dr. Jerome Conn described a patient with severe hypertension and hypokalemia and an aldosterone-secreting adenoma. The prevalence of hyperaldosteronism is increased among patients with obesity or resistant hypertension. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers reduce the secretion of aldosterone, but with chronic treatment aldosterone concentrations "escape" back to baseline values. Mineralocorticoid receptor (MR) antagonism reduces mortality in patients with heart disease who are already taking an ACE inhibitor and diuretic. In addition to affecting sodium and potassium homeostasis via classical MR-dependent pathways, aldosterone induces inflammation and causes cardiovascular remodeling and renal injury. Some of these effects involve MR-independent pathways. At the same time, ligands other than aldosterone can activate the MR. This paper reviews mechanism(s) for the proinflammatory and profibrotic effects of aldosterone and presents data indicating that endogenous aldosterone, acting at the MR, contributes to many of the pro-inflammatory and pro-fibrotic effects of angiotensin II in vivo.

  6. Aldosterone deficiency adversely affects pregnancy outcome in mice

    OpenAIRE

    2012-01-01

    Circulating aldosterone levels are increased in human pregnancy. Inadequately low aldosterone levels as present in preeclampsia, a life-threatening disease for both mother and child, are discussed to be involved in its pathogenesis or severity. Moreover, inactivating polymorphisms in the aldosterone synthase gene have been detected in preeclamptic women. Here, we used aldosterone synthase-deficient (AS(-/-)) mice to test whether the absence of aldosterone is sufficient to impair pregnancy or ...

  7. Central interactions of aldosterone and angiotensin II in aldosterone- and angiotensin II-induced hypertension.

    Science.gov (United States)

    Xue, Baojian; Beltz, Terry G; Yu, Yang; Guo, Fang; Gomez-Sanchez, Celso E; Hay, Meredith; Johnson, Alan Kim

    2011-02-01

    Many studies have implicated both angiotensin II (ANG II) and aldosterone (Aldo) in the pathogenesis of hypertension, the progression of renal injury, and cardiac remodeling after myocardial infarction. In several cases, ANG II and Aldo have been shown to have synergistic interactions in the periphery. In the present studies, we tested the hypothesis that ANG II and Aldo interact centrally in Aldo- and ANG II-induced hypertension in male rats. In rats with blood pressure (BP) and heart rate (HR) measured by DSI telemetry, intracerebroventricular (icv) infusions of the mineralocorticoid receptor (MR) antagonists spironolactone and RU28318 or the angiotensin type 1 receptor (AT1R) antagonist irbesartan significantly inhibited Aldo-induced hypertension. In ANG II-induced hypertension, icv infusion of RU28318 significantly reduced the increase in BP. Moreover, icv infusions of the reactive oxygen species (ROS) scavenger tempol or the NADPH oxidase inhibitor apocynin attenuated Aldo-induced hypertension. To confirm these effects of pharmacological antagonists, icv injections of either recombinant adeno-associated virus carrying siRNA silencers of AT1aR (AT1aR-siRNA) or MR (MR-siRNA) significantly attenuated the development of Aldo-induced hypertension. The immunohistochemical and Western blot analyses of AT1aR-siRNA- or MR-siRNA-injected rats showed a marked reduction in the expression of AT1R or MR in the paraventricular nucleus compared with scrambled siRNA rats. When animals from all studies underwent ganglionic blockade with hexamethonium, there was a smaller reduction in the fall of BP in animals receiving icv AT1R or MR antagonists. These results suggest that ANG II and Aldo interact in the brain in a mutually cooperative manner such that the functional integrity of both brain AT1R and MR are necessary for hypertension to be induced by either systemic ANG II or Aldo. The pressor effects produced by systemic ANG II or Aldo involve increased central ROS and

  8. Diagnostic evaluation of plasma aldosterone concentration to plasma renin activity ratio in primary aldosteronism

    Institute of Scientific and Technical Information of China (English)

    Huilan ZHANG; Daowen WANG

    2008-01-01

    Using the plasma aldosterone concentration to plasma renin activity ratio (PAC/PRA ratio) as the screening test of choice for primary aldosteronism in hypertensive patients, we studied the clinical character-istics and the diagnostic value of PAC/PRA ratio in primary aldosteronism. The plasma aldosterone concen-tration (PAC) and plasma renin activity (PRA) levels were measured by radioimmunoassay in 902 hypertensive patients from out-patient clinics or hospitals. One hundred and twenty-six suspected primary aldosteronism patients whose PAC/PRA ratio was > 25 ng/dL/ng/mL/ hr had a lamellar computed tomography (CT) scan in the adrenal gland and follow-up visits. The proportion of primary aldosteronism in hypertensive patients was 14% (126/902). There were 54 patients with unilateral or bilateral hyperplasia and 25 patients with adenoma according to the CT scan. 39% (49/126) of the patients with primary aldosteronism had hypokalemia. Twenty-five patients received surgical treatment. The efficacy and cure rates were 100% (25/25) and 48% (12/25), respect-ively. The effective rate of aldactone and the single-drug cure rate were 89% (48/54) and 24% (13/54), respectively. Primary aldosteronism affects over 10% of hypertensive patients in China. The PAC/PRA ratio can be considered as a routine screening test in hypertensives, especially resistant hypertensive patients and a high PAC/PRA ratio is an invaluable index in primary aldosteronism diagnosis.

  9. Detection, Diagnosis, and Treatment of Primary Aldosteronism

    Science.gov (United States)

    ... alone may not identify the cause of the overproduction. Further testing may include adrenal venous sampling. In ... one of your adrenal glands is causing the overproduction of aldosterone, it can be surgically removed. This ...

  10. Aldosterone assessment in patients with Meniere's disease

    NARCIS (Netherlands)

    Mateijsen, DJM; Kingma, CM; De Jong, PE; Wit, HP; Albers, FWJ

    2001-01-01

    Since 1938 endolymphatic hydrops has generally been accepted as the basic histopathological substrate of Meniere's disease. In animal studies it has been found that exogenous administration of aldosterone resulted in endolymphatic hydrops. Manifestations of Meniere's disease are frequently observed

  11. Aldosterone response to angiotensin II during hypoxemia

    Energy Technology Data Exchange (ETDEWEB)

    Colice, G.L.; Ramirez, G.

    1986-07-01

    Exercise stimulates the renin-angiotensin-aldosterone system (RAAS). However, increases in plasma aldosterone concentrations (PAC) are suppressed when exercise is performed at high altitude or under hypoxemic conditions. As the angiotensin-II response to high-altitude exercise is normal, it is speculated that an inhibitor, discharged during hypoxemia, acted to suppress angiotensin-II-mediated aldosterone release. A study was conducted to test this hypothesis, taking into account the measurement of the aldosterone response to exogenous angiotensin II during normoxemia and hypoxemia. It was found that the dose-response curve of PAC to angiotensin II was not significantly inhibited by the considered model of hypoxemia. The hypoxemia-mediated release of an angiotensin II inhibitor does, therefore, not explain the previous observations of PAC suppression during hypoxemic exercise. 28 references.

  12. Increased aldosterone: mechanism of hypertension in obesity.

    Science.gov (United States)

    Flynn, Colleen

    2014-05-01

    The prevalence of both obesity and hypertension are increasing worldwide. Hypertension is a common consequence of obesity. Increased central adiposity is associated with increased aldosterone levels and blood pressure in human beings. A number of small studies have shown an association between obesity-mediated hypertension and mechanisms directly linked to increased levels of aldosterone. These studies have shown a trend toward relatively greater blood pressure reduction using aldosterone-receptor blockers compared with other classes of antihypertensive agents. Other than treatment for weight loss, treatment of hypertension with specific antihypertensive medications that block or reduce aldosterone action are appropriate in obese patients. Further research is needed to understand the exact role of the adipocyte in obesity-mediated hypertension.

  13. Primary Aldosteronism and ARMC5 Variants

    Science.gov (United States)

    Zilbermint, Mihail; Xekouki, Paraskevi; Faucz, Fabio R.; Berthon, Annabel; Gkourogianni, Alexandra; Schernthaner-Reiter, Marie Helene; Batsis, Maria; Sinaii, Ninet; Quezado, Martha M.; Merino, Maria; Hodes, Aaron; Abraham, Smita B.; Libé, Rossella; Assié, Guillaume; Espiard, Stéphanie; Drougat, Ludivine; Ragazzon, Bruno; Davis, Adam; Gebreab, Samson Y.; Neff, Ryan; Kebebew, Electron; Bertherat, Jérôme; Lodish, Maya B.

    2015-01-01

    Context: Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia. Objective: We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects. Methods: Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods. Results: We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023). Conclusions: Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension. PMID:25822102

  14. 醛固酮与代谢综合征%Aldosterone and metabolic syndrome

    Institute of Scientific and Technical Information of China (English)

    李平; 陈名道

    2010-01-01

    Aldosterone and metabolic syndrome are known cardiovascular risk factors associated with increased morbidity and mortality. This review focuses on the recent advances and clinical significance of the relationship between aldosterone and each single component of metabolic syndrome. The possible role of aldosterone receptor antagonist or aldosterone synthetase inhibitor in the treatment of metabolic syndrome is discussed.%醛固酮与代谢综合征均为心血管疾病危险因子.探讨醛固酮与代谢综合征之间的关系及机制有重要意义.本文综述了醛固酮与代谢综合征各组分之间相关性的最新进展和临床意义,探讨醛固酮受体拮抗剂或醛固酮合成酶抑制剂在代谢综合征治疗中的可能作用.

  15. Localization of aldosterone-producing tumours in primary aldosteronism by adrenal and renal vein catheterization

    DEFF Research Database (Denmark)

    Lund, J O; Nielsen, M D; Giese, Jacob;

    1980-01-01

    Regional venous plasma aldosterone concentrations were determined and assessed against concurrent arterial levels in 16 patients with primary aldosteronism. The results obtained by sampling from the left adrenal vein or the left renal vein allowed correct side prediction of the presupposed adenom...

  16. Aldosterone blockade in post-acute myocardial infarction heart failure

    NARCIS (Netherlands)

    Pitt, Bertram; Ferrari, Roberto; Gheorghiade, Mihai; van Veldhuisen, Dirk J.; Krum, Henry; McMurray, John; Lopez-Sendon, Jose

    2006-01-01

    Development of heart failure (HF) or left ventricular systolic dysfunction (LVSD) significantly increases mortality post acute myocardial infarction (AMI). Aldosterone contributes to the development and progression of HF post AMI, and major guidelines now recommend aldosterone blockade in this setti

  17. Increased plasma aldosterone during atrial fibrillation declines following cardioversion

    DEFF Research Database (Denmark)

    Soeby-Land, C; Dixen, U; Therkelsen, S K;

    2011-01-01

    The renin-angiotensin-aldosterone system (RAAS) may be activated during atrial fibrillation (AF); our aim was to evaluate the level of aldosterone in patients with either permanent AF, persistent AF scheduled for cardioversion or patients in sinus rhythm (SR). We hypothesized that an increased...... level of aldosterone is found in patients with AF, decreasing in patients with restored SR....

  18. Twenty-Four-Hour Urinary Aldosterone Predicts Inappropriate Left Ventricular Mass Index in Patients with Primary Aldosteronism

    Directory of Open Access Journals (Sweden)

    Chi-Sheng Hung

    2013-01-01

    Full Text Available Objective. Primary aldosteronism (PA is associated with inappropriate left ventricular hypertrophy (LVH in relation to a given gender and body size. There is no ideal parameter to predict the presence of LVH or inappropriate LVH in patients with PA. We investigate the performance of 24-hour urinary aldosterone level, plasma renin activity and aldosterone-to-renin ratio on this task. Methods. We performed echocardiography in 106 patients with PA and 31 subjects with essential hypertension (EH in a tertiary teaching hospital. Plasma renin activity, aldosterone concentration, and 24-hour urinary aldosterone level were measured. Results. Only 24-hour urinary aldosterone was correlated with left ventricular mass index (LVMI and excess LVMI among these parameters. The multivariate analysis revealed the urinary aldosterone level as an independent predictor for LVMI and excess LVMI. Analyzing the ability of urinary aldosterone, plasma aldosterone concentration, and plasma aldosterone-to-renin ratio to identify the presence of LVH (ROC AUC = 0.701, 0.568, 0.656, resp. and the presence of inappropriate LV mass index (defined as measured LVMI in predicting LVMI ratio >135% (ROC area under curve = 0.61, 0.43, 0.493, resp. revealed the better performance of 24-hour urinary aldosterone. Conclusions. In conclusion, 24-hour urinary aldosterone level performed better to predict the presence of LVH and inappropriate LVMI in patients with PA.

  19. Aortic Cell Apoptosis in Rat Primary Aldosteronism Model

    Institute of Scientific and Technical Information of China (English)

    闫永吉; 欧阳金芝; 王超; 吴准; 马鑫; 李宏召; 徐华; 胡争; 李俊; 王保军; 史涛坪; 龚道静; 倪栋; 张旭

    2010-01-01

    This study aimed to determine whether aldosterone could induce vascular cell apoptosis in vivo.Thirty-two male rats were randomly divided into 4 groups:vehicle(control),aldosterone,aldosterone plus eplerenone or hydralazine.They were then implanted with an osmotic mini-pump that infused either aldosterone or the vehicle.Systolic blood pressure(SBP) was measured weekly by the tail-cuff method.After 8 weeks,plasma aldosterone concentration(PAC) and renin activity(PRA) were determined by radioimmunoassay.Aorti...

  20. Active renin mass concentration to determine aldosterone-to-renin ratio in screening for primary aldosteronism

    Directory of Open Access Journals (Sweden)

    Corbin F

    2011-07-01

    Full Text Available François Corbin1, Pierre Douville2, Marcel Lebel3 1Division of Biochemistry, l'Université de Sherbrooke, Sherbrooke, Quebec, Canada; 2Division of Biochemistry; 3Division of Nephrology, L'Hôtel-Dieu de Québec Hospital and l'Université Laval, Quebec, CanadaBackground: Active renin mass concentration (ARC is independent of the endogenous level of angiotensinogen, and less variable and more reproducible than plasma renin activity. Reference values for the aldosterone-to-renin ratio (ARR using ARC are still undefined. The objective of the present study was to determine the threshold of ARR using ARC measurement to screen for primary aldosteronism.Methods: A total of 211 subjects were included in the study, comprising 78 healthy normotensive controls, 95 patients with essential hypertension, and 38 patients with confirmed primary aldosteronism (20 with surgery-confirmed aldosterone-producing adenoma and 18 with idiopathic adrenal hyperplasia. Blood samples were drawn from ambulatory patients and volunteers in the mid-morning without specific dietary restriction for measuring plasma aldosterone concentration, ARC, and serum potassium.Results: Most normotensive controls and essential hypertension patients had ARR results below 100 pmol/ng, a value which corresponded to 3.3 times the median of these two groups.Conclusion: Patients with ARR values above this level should be considered for further investigation (confirmatory tests or for repeat testing should ARR values be borderline. This study indicates that ARC can be used reliably in determining ARR for primary aldosteronism screening.Keywords: primary aldosteronism, active renin mass concentration, aldosterone-to-renin ratio

  1. [Four cases of aldosterone synthase deficiency in childhood].

    Science.gov (United States)

    Collinet, E; Pelissier, P; Richard, O; Gay, C; Pugeat, M; Morel, Y; Stephan, J-L

    2012-11-01

    Neonatal salt-wasting syndromes are rare but potentially serious conditions. Isolated hypoaldosteronism is an autosomal recessive inherited disorder of terminal aldosterone synthesis, leading to selective aldosterone deficiency. Two different biochemical forms of this disease have been described, called aldosterone synthase deficiency or corticosterone methyl oxydase, types I and II. In type I, there is no aldosterone synthase activity and the 18 hydroxycorticosterone (18 OHB) level is low, whereas in type II, a residual activity of aldosterone synthase persists and 18 OHB is overproduced. We report on four patients with isolated hypoaldosteronism. In 2 of them, who were recently diagnosed with aldosterone synthase deficit, we discuss the symptoms and treatment. The 2 other patients are now adults. We discuss the long-term outcome, the quality of adult life, aldosterone synthase deficits, as well as the pathophysiology and molecular analysis.

  2. The ratios of aldosterone / plasma renin activity (ARR) versus aldosterone / direct renin concentration (ADRR).

    Science.gov (United States)

    Glinicki, Piotr; Jeske, Wojciech; Bednarek-Papierska, Lucyna; Kruszyńska, Aleksandra; Gietka-Czernel, Małgorzata; Rosłonowska, Elżbieta; Słowińska-Srzednicka, Jadwiga; Kasperlik-Załuska, Anna; Zgliczyński, Wojciech

    2015-12-01

    Primary aldosteronism (PA) is estimated to occur in 5-12% of patients with hypertension. Assessment of aldosterone / plasma renin activity (PRA) ratio (ARR) has been used as a screening test in patients suspected of PA. Direct determination of renin (DRC) and calculation of aldosterone / direct renin concentration ratio (ADRR) could be similarly useful for screening patients suspected of PA. The study included 62 patients with indication for evaluation of the renin-angiotensin-aldosterone system and 35 healthy volunteers. In all participants we measured concentrations of serum aldosterone, plasma direct renin, and PRA after a night's rest and again after walking for two hours. The concentrations of aldosterone, direct renin, and PRA were measured by isotopic methods (radioimmunoassay (RIA) / immunoradiometric assay (IRMA)). Correlations of ARR with ADRR in the supine position were r = 0.9162, r(2) = 0.8165 (p 80% and 100%, respectively) appeared for the ratios ≥ 30. We suggest that for practical and economic reasons ARR can be replaced by ADRR.

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

    Science.gov (United States)

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

    2016-10-01

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

  4. Reviving the use of aldosterone inhibitors in treating hypertension in obesity.

    Science.gov (United States)

    Huby, Anne-Cecile; Belin De Chantemèle, Eric J

    2015-11-01

    Obesity is a multifactorial disease associated with hypertension. In the obese population, the incidence of hypertension is high and resistant hypertension is commonly observed. Mechanisms to explain the resistance to current antihypertensive treatments are still poorly understood. Emerging knowledge of the role of aldosterone in controlling blood pressure in obesity may have therapeutic benefit. Mineralocorticoid receptor (MR) inhibitors are currently used as the fourth line of treatment. Clinical studies summarized in this short review suggest that MR antagonists have a strong efficacy in decreasing blood pressure in the hypertensive obese population and could be used as a primary antihypertensive in obesity.

  5. The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells.

    Science.gov (United States)

    Pan, Zhi-qiang; Xie, Ding; Choudhary, Vivek; Seremwe, Mutsa; Tsai, Ying-Ying; Olala, Lawrence; Chen, Xunsheng; Bollag, Wendy B

    2014-08-25

    Pioglitazone belongs to the class of drugs called thiazolidinediones (TZDs), which are widely used as insulin sensitizers in the treatment of diabetes. A major side effect of TZDs is fluid retention. The steroid hormone aldosterone also promotes sodium and fluid retention; however, the effect of pioglitazone on aldosterone production is controversial. We analyzed the effect of pioglitazone alone and in combination with angiotensin II (AngII) on the late rate-limiting step of adrenocortical steroidogenesis in human adrenocortical carcinoma HAC15 cells. Treatment with pioglitazone for 24 h significantly increased the expression of CYP11B2 and enhanced AngII-induced CYP11B2 expression. Despite the observed changes in mRNA levels, pioglitazone significantly inhibited AngII-induced aldosterone production and CYP11B2 protein levels. On the other hand, pioglitazone stimulated the expression of the unfolded protein response (UPR) marker DDIT3, with this effect occurring at early times and inhibitable by the PPARγ antagonist GW9962. The levels of DDIT3 (CHOP) and phospho-eIF2α (Ser51), a UPR-induced event that inhibits protein translation, were also increased. Thus, pioglitazone promotes CYP11B2 expression but nevertheless inhibits aldosterone production in AngII-treated HAC15 cells, likely by blocking global protein translation initiation through DDIT3 and phospho-eIF2α. In contrast, pioglitazone promoted AngII-induced CYP11B1 expression and cortisol production. Since cortisol enhances lipolysis, this result suggests the possibility that PPARs, activated by products of fatty acid oxidation, stimulate cortisol secretion to promote utilization of fatty acids during fasting. In turn, the ability of pioglitazone to stimulate cortisol production could potentially underlie the effects of this drug on fluid retention.

  6. Mechanisms underlying rapid aldosterone effects in the kidney.

    LENUS (Irish Health Repository)

    Thomas, Warren

    2012-02-01

    The steroid hormone aldosterone is a key regulator of electrolyte transport in the kidney and contributes to both homeostatic whole-body electrolyte balance and the development of renal and cardiovascular pathologies. Aldosterone exerts its action principally through the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues. Aldosterone also stimulates the activation of protein kinases and secondary messenger signaling cascades that act independently on specific molecular targets in the cell membrane and also modulate the transcriptional action of aldosterone through MR. This review describes current knowledge regarding the mechanisms and targets of rapid aldosterone action in the nephron and how aldosterone integrates these responses into the regulation of renal physiology.

  7. Mechanisms underlying rapid aldosterone effects in the kidney.

    LENUS (Irish Health Repository)

    Thomas, Warren

    2011-03-17

    The steroid hormone aldosterone is a key regulator of electrolyte transport in the kidney and contributes to both homeostatic whole-body electrolyte balance and the development of renal and cardiovascular pathologies. Aldosterone exerts its action principally through the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues. Aldosterone also stimulates the activation of protein kinases and secondary messenger signaling cascades that act independently on specific molecular targets in the cell membrane and also modulate the transcriptional action of aldosterone through MR. This review describes current knowledge regarding the mechanisms and targets of rapid aldosterone action in the nephron and how aldosterone integrates these responses into the regulation of renal physiology.

  8. Aldosterone and the heart: still an unresolved issue?

    Directory of Open Access Journals (Sweden)

    Cristiana eCatena

    2014-10-01

    Full Text Available Receptors for mineralocorticoid hormones are expressed in myocardial cells and evidence obtained in animal studies suggests that activation of these receptors causes cardiac damage independent from blood pressure levels. In the last years, many of the issues related to the effects of aldosterone on the heart have received convincing answers and clinical investigation has focused on a variety of conditions including systolic and diastolic heart failure, arrhythmia, primary hypertension, and primary aldosteronism. Some issues, however, await clarification in order to obtain better understanding of what could be the role of aldosterone blockade in prevention and treatment of cardiovascular diseases. In this article, we overview the most recent findings of animal studies that have examined the contribution of aldosterone to cardiac function and clinical studies that have investigated the influence of aldosterone on left ventricular structure and function in the setting of primary hypertension and primary aldosteronism.

  9. Purinergic Inhibition of ENaC Produces Aldosterone Escape

    OpenAIRE

    Stockand, James D.; Mironova, Elena; Bugaj, Vladislav; Rieg, Timo; Insel, Paul A.; Vallon, Volker; Peti-Peterdi, Janos; Pochynyuk, Oleh

    2010-01-01

    The mechanisms underlying “aldosterone escape,” which refers to the excretion of sodium (Na+) during high Na+ intake despite inappropriately increased levels of mineralocorticoids, are incompletely understood. Because local purinergic tone in the aldosterone-sensitive distal nephron downregulates epithelial Na+ channel (ENaC) activity, we tested whether this mechanism mediates aldosterone escape. Here, urinary ATP concentration increased with dietary Na+ intake in mice. Physiologic concentrat...

  10. Aldosterone synthase inhibitors in hypertension: current status and future possibilities

    OpenAIRE

    Milan Hargovan; Albert Ferro

    2014-01-01

    The renin-angiotensin aldosterone system is a critical mechanism for controlling blood pressure, and exerts most of its physiological effects through the action of angiotensin II. In addition to increasing blood pressure by increasing vascular resistance, angiotensin II also stimulates aldosterone secretion from the adrenal gland. Aldosterone acts to cause an increase in sodium and water reabsorption, thus elevating blood pressure. Although treatment with angiotensin converting enzyme inhibit...

  11. Aldosterone and Its Blockade: A Cardiovascular and Renal Perspective

    OpenAIRE

    Lahera, V.; Cachofeiro, V.; Balfagon, G.; J.L. Rodicio

    2006-01-01

    Aldosterone not only contributes to salt and water homeostasis, but also exerts direct cardiovascular and renal effects. Numerous experimental and clinical studies indicate that aldosterone participate in cardiac alterations associated with hypertension, heart failure, diabetes and other pathological entities. It is important to mention that dietary salt is a key factor in aldosterone-mediated cardiovascular damage, since damage was moreevident in animals on a high-salt diet than animals on ...

  12. A critical review of the evidence supporting aldosterone in the etiology and its blockade in the treatment of obesity-associated hypertension.

    Science.gov (United States)

    Byrd, J B; Brook, R D

    2014-01-01

    Obesity is epidemic and is associated with increased blood pressure, which often manifests as treatment-resistant hypertension. Mineralocorticoids have been hypothesized to have a pathogenic role in human obesity-associated hypertension. In this review, we critically appraise the existing data regarding aldosterone in the pathophysiology and treatment of obesity-associated hypertension. We begin by reviewing the mechanisms by which obesity may increase mineralocorticoid activity. We then discuss human studies of plasma and urine aldosterone in obesity and with weight loss. From these studies, we conclude that aldosterone is often, but not always, mildly increased in obesity. Further study is needed to define circumstances in which aldosterone is increased in obesity. We discuss clinical studies in which measures of body size or weight were evaluated as potential predictors of response to mineralocorticoid receptor antagonists. In addition, we review three randomized, controlled clinical trials that exemplify a rigorous approach to determining the role of mineralocorticoid activity in a human disease. We propose that a similar clinical trial is warranted in order to definitively clarify the role of inappropriate mineralocorticoid activity in the etiology of human obesity-associated hypertension. Finally, we conclude that additional research is needed into the possible role of non-aldosterone mineralocorticoids in human obesity-associated hypertension.

  13. 醛固酮对靶器官心脏的损伤作用%Cardiac Injury Caused by Aldosterone

    Institute of Scientific and Technical Information of China (English)

    张美娟

    2011-01-01

    醛固酮可由心脏及血管生成并在心血管系统的调节及多种心血管疾病的致病过程中起重要的作用,且独立于通过调节盐水平衡而介导的血压升高.醛固酮受体拮抗剂如螺内酯及依普利酮可以显著降低心力衰竭患者的发病率及病死率.醛固酮与盐皮质激素受体结合并通过多种机制造成靶器官心脏的损伤.心脏组织醛固酮与盐皮质激素受体结合有赖于11β-羟基类固醇脱氢酶2型的表达,且其心脏损伤与食盐摄入水平有关,新近研究显示醛固酮在心脏电重构中起重要作用.%Aldosterone, which can be generated by the heart and blood vessels,also plays an important role in pathogenesis of several cardiovascular diseases, and the effect is independent from the elevation of blood pressure which is mediated by water and sodium regulation. Clinical studies show that aldosterone receptor antagonists such as spironolactone and eplerenone reduced the incidence of morbidity and mortality of patients with heart failure significantly. The combination of aldosterone and mineralocorticoid receptor( MR ), which is dependent on the expression of 11 (3-hydroxysteroid dehydrogenase type 2, injures the heart through a variety of mechanisms, and the heart injury of aldosterone is correlated with salt intake. Recent study showed that aldosterone play an important role in cardiac electrical remodeling.

  14. Regulation of Adrenal Aldosterone Production by Serine Protease Prostasin

    Directory of Open Access Journals (Sweden)

    Takehiro Ko

    2010-01-01

    Full Text Available A serine protease prostasin has been demonstrated to have a pivotal role in the activation of the epithelial sodium channel. Systemic administration of adenovirus carrying human prostasin gene in rats resulted in an increase in plasma prostasin and aldosterone levels. However, the mechanism by which the elevation of prostasin levels in the systemic circulation stimulated the plasma aldosterone levels remains unknown. Therefore, we examined if prostasin increases the aldosterone synthesis in a human adrenocortical cell line (H295R cells. Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. Prostasin significantly increased both CYP11B2 mRNA expression and aldosterone production in a dose-dependent manner. Surprisingly, treatment with camostat mesilate, a potent prostasin inhibitor, had no effect on the aldosterone synthesis by prostasin and also a protease-dead mutant of prostasin significantly stimulated the aldosterone production. A T-type/L-type calcium channel blocker and a protein kinase C (PKC inhibitor significantly reduced the aldosterone synthesis by prostasin. Our findings suggest a stimulatory effect of prostasin on the aldosterone synthesis by adrenal gland through the nonproteolytic action and indicate a new role of prostasin in the systemic circulation.

  15. Early autophagy activation inhibits podocytes from apoptosis induced by aldosterone

    Institute of Scientific and Technical Information of China (English)

    王文琰

    2013-01-01

    Objective To explore the protection of early autoph-agy activation on podocyte injury induced by aldosterone.Methods In vitro cultured mouse podocyte clones(MPC5) were treated with aldosterone for 6,12,24,48 hrespectively. Apoptosis of podocytes was detected by

  16. Prevalence of Malignancies in Patients With Primary Aldosteronism.

    Science.gov (United States)

    Lang, K; Weber, K; Quinkler, M; Dietz, A S; Wallaschofski, H; Hannemann, A; Friedrichs, N; Rump, L C; Heinze, B; Fuss, C T; Quack, I; Willenberg, H S; Reincke, M; Allolio, B; Hahner, S

    2016-04-01

    In the multicenter MEPHISTO study, the prevalence of benign and malignant tumors has been investigated in 335 patients with confirmed primary aldosteronism and compared to matched controls. Compared to hypertensive controls, the prevalence of malignancies was positively correlated with aldosterone levels, tended to be higher in PA patients, but did not differ significantly.

  17. Aldosterone deficiency adversely affects pregnancy outcome in mice.

    Science.gov (United States)

    Todkar, Abhijeet; Di Chiara, Marianna; Loffing-Cueni, Dominique; Bettoni, Carla; Mohaupt, Markus; Loffing, Johannes; Wagner, Carsten A

    2012-10-01

    Circulating aldosterone levels are increased in human pregnancy. Inadequately low aldosterone levels as present in preeclampsia, a life-threatening disease for both mother and child, are discussed to be involved in its pathogenesis or severity. Moreover, inactivating polymorphisms in the aldosterone synthase gene have been detected in preeclamptic women. Here, we used aldosterone synthase-deficient (AS(-/-)) mice to test whether the absence of aldosterone is sufficient to impair pregnancy or even to cause preeclampsia. AS(-/-) and AS(+/+) females were mated with AS(+/+) and AS(-/-) males, respectively, always generating AS(+/-) offspring. With maternal aldosterone deficiency in AS(-/-) mice, systolic blood pressure was low before and further reduced during pregnancy with no increase in proteinuria. Yet, AS(-/-) had smaller litters due to loss of fetuses as indicated by a high number of necrotic placentas with massive lymphocyte infiltrations at gestational day 18. Surviving fetuses and their placentas from AS(-/-) females were smaller. High-salt diet before and during pregnancy increased systolic blood pressure only before pregnancy in both genotypes and abolished the difference in blood pressure during late pregnancy. Litter size from AS(-/-) was slightly improved and the differences in placental and fetal weights between AS(+/+) and AS(-/-) mothers disappeared. Overall, an increased placental efficiency was observed in both groups paralleled by a normalization of elevated HIF1α levels in the AS(-/-) placentas. Our results demonstrate that aldosterone deficiency has profound adverse effects on placental function. High dietary salt intake improved placental function. In this animal model, aldosterone deficiency did not cause preeclampsia.

  18. Adrenal vein sampling in the diagnosis of aldosteronism

    Directory of Open Access Journals (Sweden)

    Deipolyi AR

    2015-06-01

    Full Text Available Amy R Deipolyi,1 Rahmi Oklu2 1Vascular and Interventional Radiology, NYU Langone Medical Center, New York, NY, USA; 2Interventional Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Abstract: Primary aldosteronism causes 15%–25% of cases of drug-resistant hypertension. Adrenal vein sampling (AVS is a procedure entailing the measurement of aldosterone from both adrenal veins, to diagnose an adrenal source of excess aldosterone secretion. Because unilateral adrenal etiologies of primary aldosteronism may be surgically resected, identifying these sources by venous sampling is critical. Technical aspects of the procedure are reviewed, with emphasis on strategies to avoid common difficulties during AVS. Keywords: primary aldosteronism, hypertension, venous sampling, adrenal adenoma

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

    Science.gov (United States)

    Erne, P

    1996-02-20

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

  20. GABAB antagonists

    DEFF Research Database (Denmark)

    Frydenvang, Karla Andrea; Hansen, J J; Krogsgaard-Larsen, P

    1994-01-01

    Phaclofen, which is the phosphonic acid analogue of the GABAB agonist (RS)-3-(4-chlorophenyl)-4-aminobutyric acid (baclofen), is a GABAB antagonist. As part of our studies on the structural requirements for activation and blockade of GABAB receptors, we have resolved phaclofen using chiral chroma...

  1. Renin and aldosterone at high altitude in man.

    Science.gov (United States)

    Keynes, R J; Smith, G W; Slater, J D; Brown, M M; Brown, S E; Payne, N N; Jowett, T P; Monge, C C

    1982-01-01

    Measurements have been made of hormonal changes relevant to salt and water balance during prolonged exposure to hypoxia to improve our understanding of the syndrome of acute mountain sickness. We have attempted to delineate the detailed inter-relationships between the renin-aldosterone and the vasopressin systems by a metabolically controlled study, involving an orthostatic stress (45 degrees head-up tilt) and an injection of a standard dose of ACTH to test adrenal responsiveness. Three Caucasian medical students underwent a 7-day equilibration at 150 m (Lima, Peru), followed by a 6-day sojourn at 4350 m (Cerro de Pasco, Peru) and a final 7 days at 150 m. Measurements were made of sodium and potassium balance, body weight and the 24-h renal excretion of vasopressin, cortisol and aldosterone 18-glucuronide. These variables showed little change, except for that of aldosterone 18-glucuronide, which fell sharply at altitude and rebounded even more sharply on return to sea level. At altitude, basal plasma levels of renin activity and aldosterone fell, and the response to orthostasis was attenuated, but the fall of plasma renin activity, as compared to plasma aldosterone, was delayed; on return to sea level this dissociation was exacerbated with the return of normal renin responsiveness lagging behind that of aldosterone. We suggest that unknown factors which dissociate the orthodox renin-aldosterone relationship, other than the activity of the angiotensin I-converting enzyme, are operative on exposure to hypoxia.

  2. Aldosterone and mortality in hemodialysis patients: role of volume overload.

    Directory of Open Access Journals (Sweden)

    Szu-Chun Hung

    Full Text Available BACKGROUND: Elevated aldosterone is associated with increased mortality in the general population. In patients on dialysis, however, the association is reversed. This paradox may be explained by volume overload, which is associated with lower aldosterone and higher mortality. METHODS: We evaluated the relationship between aldosterone and outcomes in a prospective cohort of 328 hemodialysis patients stratified by the presence or absence of volume overload (defined as extracellular water/total body water >48%, as measured with bioimpedance. Baseline plasma aldosterone was measured before dialysis and categorized as low (280 pg/mL. RESULTS: Overall, 36% (n = 119 of the hemodialysis patients had evidence of volume overload. Baseline aldosterone was significantly lower in the presence of volume overload than in its absence. During a median follow-up of 54 months, 83 deaths and 70 cardiovascular events occurred. Cox multivariate analysis showed that by using the low aldosterone as the reference, high aldosterone was inversely associated with decreased hazard ratios for mortality (0.49; 95% confidence interval, 0.25-0.76 and first cardiovascular event (0.70; 95% confidence interval, 0.33-0.78 in the presence of volume overload. In contrast, high aldosterone was associated with an increased risk for mortality (1.97; 95% confidence interval, 1.69-3.75 and first cardiovascular event (2.01; 95% confidence interval, 1.28-4.15 in the absence of volume overload. CONCLUSIONS: The inverse association of aldosterone with adverse outcomes in hemodialysis patients is due to the confounding effect of volume overload. These findings support treatment of hyperaldosteronemia in hemodialysis patients who have achieved strict volume control.

  3. Raised Plasma Aldosterone and Natriuretic Peptides in Atrial Fibrillation

    DEFF Research Database (Denmark)

    Dixen, Ulrik; Ravn, Lasse Steen; Soeby-Rasmussen, Christian;

    2006-01-01

    BACKGROUND AND AIMS: During atrial fibrillation (AF), the renin-angiotensin-aldosterone system (RAAS) may be activated. In this study, our aim was to evaluate at a long-term follow-up visit the levels of plasma aldosterone and natriuretic peptides as markers of neurohormonal remodeling in patients...... with earlier, documented AF in relation to present heart rhythm, clinical data, and the left ventricular ejection fraction (LVEF). We hypothesized that increased levels of aldosterone and natriuretic peptides were significantly associated with present AF as markers of RAAS activation during the arrhythmia...

  4. Raised plasma aldosterone and natriuretic peptides in atrial fibrillation

    DEFF Research Database (Denmark)

    Dixen, U; Ravn, L; Soeby-Rasmussen, C;

    2007-01-01

    During atrial fibrillation (AF), the renin-angiotensin-aldosterone system (RAAS) may be activated. In this study, our aim was to evaluate at a long-term follow-up visit the levels of plasma aldosterone and natriuretic peptides as markers of neurohormonal remodeling in patients with earlier......, documented AF in relation to present heart rhythm, clinical data, and the left ventricular ejection fraction (LVEF). We hypothesized that increased levels of aldosterone and natriuretic peptides were significantly associated with present AF as markers of RAAS activation during the arrhythmia....

  5. Electrical and myocardial remodeling in primary aldosteronism

    Directory of Open Access Journals (Sweden)

    Mario eCurione

    2014-11-01

    Full Text Available Objective and design: primary aldosteronism (PA represents the most common cause of secondary hypertension. An higher risk of cardiovascular events has been reported in patients with PA than otherwise similar patients with essential hypertension (EH. At today few studies has been investigated the electrocardiographic changes in PA patients compared to EH patients.Methods: to investigate the electrocardiographic changes and heart remodeling in PA we enrolled 61 consecutive patients, 30 with PA (12 with aldosterone producing adenoma-APA and 18 with bilateral adrenal hyperplasia-IHA and 30 with EH. In all subjects electrelectrocardiographic parameters were evaluated from 12-lead electrocardiograms and heart remodeling with echocardiogram.Results: no significant differences in age, sex , body mass index (BMI and blood pressure were found in two groups. The P wave and PR interval duration were significantly prolonged in patientswith PA respect to EH (p< 0.003 and p< 0.002, respectively. First degree atrioventricular block was present in 16% patient with PA and only in 3.2% patients with EH. In PA patients the interventricular septum thickness (IVST correlated with left ventricular mass indecized (LVMi (r= 0.54; p< 0.04, and with PR duration (r= 0.51; p< 0.03. Left ventricular hypertrophy (LVH was present in 53% patients with PA and in 26% patients with EH (χ2 p<0.03.Conclusions: in this case-control study, patients with PA show more anatomic and electrical heart remodeling than those with EH. We hypothesize that in patients with PA these cardiac changes may play a role for the increased risk of future cardiovascular events.

  6. Pretreatment with aldosterone or corticosterone blocks the memory-enhancing effects of nimodipine, captopril, CGP 37,849, and strychnine in mice.

    Science.gov (United States)

    Mondadori, C; Gentsch, C; Hengerer, B; Ducret, T; Borkowski, J; Racine, A; Lederer, R; Haeusler, A

    1992-01-01

    Oral pretreatment with aldosterone or corticosterone blocked the memory-enhancing effects of the calcium antagonist nimodipine, the ACE inhibitor captopril, the NMDA blocker CGP 37,849, and the glycine antagonist strychnine in a passive-avoidance test in mice. The memory-disturbing effects of phenobarbitone, diazepam, CGP 37,849 and scopolamine were not influenced by the hormonal pretreatment. These findings could indicate the involvement of a steroid-sensitive mechanism in drug-induced improvement of memory. In the light of clinical observations showing elevated cortisol levels in Alzheimer patients, the results might also explain why only a limited number of these patients respond to therapy with memory enhancers.

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

    Science.gov (United States)

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

    2016-08-01

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

  8. Global- and renal-specific sympathoinhibition in aldosterone hypertension.

    Science.gov (United States)

    Lohmeier, Thomas E; Liu, Boshen; Hildebrandt, Drew A; Cates, Adam W; Georgakopoulos, Dimitrios; Irwin, Eric D

    2015-06-01

    Recent technology for chronic electric activation of the carotid baroreflex and renal nerve ablation provide global and renal-specific suppression of sympathetic activity, respectively, but the conditions for favorable antihypertensive responses in resistant hypertension are unclear. Because inappropriately high plasma levels of aldosterone are prevalent in these patients, we investigated the effects of baroreflex activation and surgical renal denervation in dogs with hypertension induced by chronic infusion of aldosterone (12 μg/kg per day). Under control conditions, basal values for mean arterial pressure and plasma norepinephrine concentration were 100±3 mm Hg and 134±26 pg/mL, respectively. By day 7 of baroreflex activation, plasma norepinephrine was reduced by ≈40% and arterial pressure by 16±2 mm Hg. All values returned to control levels during the recovery period. Arterial pressure increased to 122±5 mm Hg concomitant with a rise in plasma aldosterone concentration from 4.3±0.4 to 70.0±6.4 ng/dL after 14 days of aldosterone infusion, with no significant effect on plasma norepinephrine. After 7 days of baroreflex activation at control stimulation parameters, the reduction in plasma norepinephrine was similar but the fall in arterial pressure (7±1 mm Hg) was diminished (≈55%) during aldosterone hypertension when compared with control conditions. Despite sustained suppression of sympathetic activity, baroreflex activation did not have central actions to inhibit either the stimulation of vasopressin secretion or drinking induced by increased plasma osmolality during chronic aldosterone infusion. Finally, renal denervation did not attenuate aldosterone hypertension. These findings suggest that aldosterone excess may portend diminished blood pressure lowering to global and especially renal-specific sympathoinhibition during device-based therapy.

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

    Science.gov (United States)

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

    2016-02-01

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

  10. 醛固酮诱导大鼠肾脏衰老机制研究%Mechanism of aldosterone induced rat kdney senescence

    Institute of Scientific and Technical Information of China (English)

    范愈燕; 孙永新; 支楠; 张善东; 黄雯; 张梅; 西山成

    2013-01-01

    目的 观察醛固酮是否诱导肾脏衰老.方法 将大鼠右肾切除后随机分为4组:对照组(n=10)、模型组(n=8)、依普利酮组(100 mg·kg-1·d-1;n=8)及肼苯哒嗪组(80 mg· L-1,饮用;n=10);除对照组外,其余各组分别泵入醛固酮(0.75 μg·h-1),观察5周后肾脏衰老改变.结果 醛固酮可诱导5周龄的大鼠肾组织衰老标记物β-ga1、p53和p21表达升高,SIRT1基因表达下降,伴高血压及蛋白尿、N-乙酰基-β-D氨基葡萄糖苷酶(NAG)的排泄率增加,这些变化可以被依普利酮阻断,但是肼苯哒嗪影响不大.结论 醛固酮诱导肾小管上皮细胞损伤和衰老是通过醛固酮受体和p21依赖的途径.%Objective To investigate whether aldosterone induces cell senescence in the kidney. Methods Rats were randomly separated to vehicle (n = 10) ; aldosterone (0. 75 μg · h-1 ; n=8) ; aldosterone + eplerenone (100mg · kg-1 · d-1 ; n = 8 ) ; aldosterone + hydralazine (80 mg · L-1 in drinking water; n - 10). Results Aldosterone induced rats for 5 weeks exhibited by increased expression of senescence - associated β - galactosidase , p53 and cyclin - dependent kinase inhibitor ( p21) , and decreased expression of SIRT1. While, rats also showed hypertension and increased urinary excretion rates of proteins and N - acetyl - β - D - glucosaminidase by aldosterone infusion. These changes were abolished by eplerenone, a mineralocorticoid receptor (MR) antagonist, but unaffected by hydralazine (80 mg/liter in drinking water). Conclusion These findings indicate that aldosterone induces renal senescence in proximal tubular cells via the MR and p21 - dependent pathway, which may be involved in aldosterone - induced renal injury.

  11. Effects of gender on screening value of aldosterone-renin ratio for primary aldosteronism

    Directory of Open Access Journals (Sweden)

    Ye-qiong SONG

    2017-02-01

    Full Text Available Objective To explore the potential influence of gender on screening value of aldosterone-renin ratio (ARR for primary aldosteronism (PA. Methods The biochemical parameters were collected of 451 PA patients and 300 essential hypertension (EH patients who were diagnosed in the General Hospital of PLA from 1992 to 2014. Each group was then divided into two groups by gender. The clinical characteristics were compared and then the receiver operating characteristic curve (ROC was conducted to evaluate the best cut-off value. Results The plasma aldosterone concentration (PAC, serum sodium and ARR were much higher, but the plasma rennin activity (PRA, serum potassium and BMI were much lower in PA patients than in EH patients (P0.05. The best cut-off value of ARR in male PA patients was 19.11, the relevant area under the curve (AUC was 0.968, the sensitivity and specificity was 92.44% and 93.08%, and the Youden index (YI was 0.86. The best cut-off value of ARR in female PA patients was 27.26, with AUC 0.956, sensitivity 92.07%, specificity 90.00% and YI 0.82, respectively. If the cut-off value was set at 27.26 in males, the specificity would rise a little, but the sensitivity and YI would sharply decrease. Similarly, the sensitivity would increase a little but the specificity and YI would fall substantially if the cut-off value in females was set at 19.11. The best cut-off value of ARR in men was smaller than the official value recommended by guidelines. Conclusion Gender is an important factor should be considered while ARR is used in PA screening, and the cut-off value of ARR in screening female PA patients should be setting higher. DOI: 10.11855/j.issn.0577-7402.2017.01.10

  12. Molecular and cellular mechanisms of aldosterone producing adenoma development

    Directory of Open Access Journals (Sweden)

    Sheerazed eBoulkroun

    2015-06-01

    Full Text Available Primary aldosteronism (PA is the most common form of secondary hypertension with an estimated prevalence of ~10% in referred patients. PA occurs as a result of a dysregulation of the normal mechanisms controlling adrenal aldosterone production. It is characterized by hypertension with low plasma renin and elevated aldosterone and often associated with hypokalemia. The two major causes of PA are unilateral aldosterone producing adenoma (APA and bilateral adrenal hyperplasia, accounting together for ~95% of cases. In addition to the well-characterized effect of excess mineralocorticoids on blood pressure, high levels of aldosterone also have cardiovascular, renal and metabolic consequences. Hence, long-term consequences of PA include increased risk of coronary artery disease, myocardial infarction, heart failure and atrial fibrillation. Despite recent progress in the management of patients with PA, critical issues related to diagnosis, subtype differentiation and treatment of non-surgically correctable forms still persist. A better understanding of the pathogenic mechanisms of the disease should lead to the identification of more reliable diagnostic and prognostic biomarkers for a more sensitive and specific screening and new therapeutic options. In this review we will summarize our current knowledge on the molecular and cellular mechanisms of APA development. On one hand, we will discuss how various animal models have improved our understanding of the pathophysiology of excess aldosterone production. On the other hand, we will summarize the major advances made during the last few years in the genetics of APA due to transcriptomic studies and whole exome sequencing. The identification of recurrent and somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D and ATPases (ATP1A1 and ATP2B3 allowed highlighting the central role of calcium signaling in autonomous aldosterone production by the adrenal.

  13. Prostaglandins, renin, aldosterone, and catecholamines in preeclampsia.

    Science.gov (United States)

    Pedersen, E B; Christensen, N J; Christensen, P; Johannesen, P; Kornerup, H J; Kristensen, S; Lauritsen, J G; Leyssac, P P; Rasmussen, A B; Wohlert, M

    1983-01-01

    Urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), plasma concentrations of renin (PRC), aldosterone (PAC), noradrenaline (PNA) and adrenaline (PA) were determined in the third trimester of pregnancy, 5 days and 3 months after delivery in preeclampsia and normotensive pregnant and non-pregnant control subjects. PGE2 was higher in pregnant control subjects than in non-pregnant subjects, but reduced to non-pregnant level in preeclampsia. PGF2 alpha was the same in preeclampsia and normotensive pregnancy but higher than in the non-pregnant group. PRC and PAC were increased during pregnancy, but considerably lesser in preeclampsia than during normotensive pregnancy. PNA and PA were the same in all three groups. All parameters were normal 3 months after delivery. There were no correlations between any of the hormones and blood pressure in any of the groups. PGE2 was positively correlated to PRC. The lack of renal PGE2 in preeclampsia might be responsible for the decrease in renal blood flow and sodium excretion, and the changes in PRC and PAC are supposed to be secondary to changes in PGE2. It is hypothesised that preeclampsia is a state of prostaglandin deficiency.

  14. The mineralocorticoid receptor-p38MAPK-NFκB or ERK-Sp1 signal pathways mediate aldosterone-stimulated inflammatory and profibrotic responses in rat vascular smooth muscle cells

    Institute of Scientific and Technical Information of China (English)

    Chuan-jiang ZHU; Qing-qing WANG; Jun-lan ZHOU; Han-zhi LIU; Fang HUA; Hong-zheng YANG; Zhuo-wei HU

    2012-01-01

    Aim:To explore the signalling pathways involved in aldosterone-induced inflammation and fibrosis in rat vascular smooth muscle cells (VSMCs).Methods:Using Western blotting and real-time RT-PCR,we investigated the effects of aldosterone on the expression of cyclooxygenase-2 (Cox-2) and IL-6,two important proinflammatory factors,and TGFβ1,a critical profibrotic factor,in VSMCs.Results:Aldosterone treatment significantly increased the expression of Cox-2 and IL-6 and activation of p38MAPK and NF-κB.The expression of both Cox-2 and IL-6 could be blocked by the mineralocorticoid receptor (MR) antagonist spironolactone and the p38MAPK inhibitor SB203580.Also,the rapid phosphorylation of p38MAPK could be suppressed by SB203580 but not by spironolactone,implicating in nongenomic effects of aldosterone.Similar to SB203580 and spironolactone,the NF-κB inhibitor α-p-tosyl-L-lysine chloromethyl ketone (TLCK) markedly attenuated expression of Cox-2,indicating that MR,p38MAPK and NF-KB are associated with aldosterone-induced inflammatory responses.Furthermore,aldosterone enhanced expression of TGFβ1 in rat VSMCs.This result may be related to activation of the MR/ERK-Sp1 signalling pathway because PD98059,an ERK1/2 inhibitor,significantly blocked the rapid phosphorylation of ERK1/2 and function of Sp1 and led to reduced expression of TGFβ1.Spironolactone was also shown to significantly inhibit TGFβ1 and Sp1 expression but not ERK1/2 phosphorylation.Conclusion:These results suggest that aldosterone-induced inflammatory responses and fibrotic responses may be mediated by the MR/p38MAPK-NF-κB pathways and the MR/ERK-Sp1 pathways in VSMCs,respectively.

  15. The Role of Aldosterone in Obesity-Related Hypertension.

    Science.gov (United States)

    Kawarazaki, Wakako; Fujita, Toshiro

    2016-04-01

    Obese subjects often have hypertension and related cardiovascular and renal diseases, and this has become a serious worldwide health problem. In obese subjects, impaired renal-pressure natriuresis causes sodium retention, leading to the development of salt-sensitive hypertension. Physical compression of the kidneys by visceral fat and activation of the sympathetic nervous system, renin-angiotensin systems (RAS), and aldosterone/mineralocorticoid receptor (MR) system are involved in this mechanism. Obese subjects often exhibit hyperaldosteronism, with increased salt sensitivity of blood pressure (BP). Adipose tissue excretes aldosterone-releasing factors, thereby stimulating aldosterone secretion independently of the systemic RAS, and aldosterone/MR activation plays a key role in the development of hypertension and organ damage in obesity. In obese subjects, both salt sensitivity of BP, enhanced by obesity-related metabolic disorders including aldosterone excess, and increased dietary sodium intake are closely related to the incidence of hypertension. Some salt sensitivity-related gene variants affect the risk of obesity, and together with salt intake, its combination is possibly associated with the development of hypertension in obese subjects. With high salt levels common in modern diets, salt restriction and weight control are undoubtedly important. However, not only MR blockade but also new diagnostic modalities and therapies targeting and modifying genes that are related to salt sensitivity, obesity, or RAS regulation are expected to prevent obesity and obesity-related hypertension.

  16. Purinergic inhibition of ENaC produces aldosterone escape.

    Science.gov (United States)

    Stockand, James D; Mironova, Elena; Bugaj, Vladislav; Rieg, Timo; Insel, Paul A; Vallon, Volker; Peti-Peterdi, Janos; Pochynyuk, Oleh

    2010-11-01

    The mechanisms underlying "aldosterone escape," which refers to the excretion of sodium (Na(+)) during high Na(+) intake despite inappropriately increased levels of mineralocorticoids, are incompletely understood. Because local purinergic tone in the aldosterone-sensitive distal nephron downregulates epithelial Na(+) channel (ENaC) activity, we tested whether this mechanism mediates aldosterone escape. Here, urinary ATP concentration increased with dietary Na(+) intake in mice. Physiologic concentrations of ATP decreased ENaC activity in a dosage-dependent manner. P2Y(2)(-/-) mice, which lack the purinergic receptor, had significantly less increased Na(+) excretion than wild-type mice in response to high-Na(+) intake. Exogenous deoxycorticosterone acetate and deletion of the P2Y(2) receptor each modestly increased the resistance of ENaC to changes in Na(+) intake; together, they markedly increased resistance. Under the latter condition, ENaC could not respond to changes in Na(+) intake. In contrast, as a result of aldosterone escape, wild-type mice had increased Na(+) excretion in response to high-Na(+) intake regardless of the presence of high deoxycorticosterone acetate. These data suggest that control of ENaC by purinergic signaling is necessary for aldosterone escape.

  17. 醛固酮促进心室成纤维细胞增殖作用%THE EFFECT OF ALDOSTERONE OF PROMOTION ON PROLIFERATION OF VENTRICULAR FIBROBLASTS

    Institute of Scientific and Technical Information of China (English)

    龚素珍; 刘培庆; 鲁伟; 谈智; 符史干; 潘敬运

    2001-01-01

    To study the effect of promoting aldosterone on proliferation of ventricular fibroblasts. Methods: Assay of [3H]-TdR incorporat ion rate and RT-PCR were used.Results: Aldosterone could promote [ 3H]-TdR incoporation of ventricular fibrolasts,the effective dose of aldost erone was among (1×10-9~1×10-6)mol/L,and had dose-dependent mann er,the c-fos gene was expressed after stimulated by aldosterone for 15 min,and studied the highest in 1 h,then reduced later.Spironolactone,aldosterone recepto r antagonist could block the effect of aldosterone.Conclusion: Aldos terone promotes the proliferation of ventricular fibroblasts,mediated by aldoste rone receptor.%目的:探讨醛固酮促进心室成纤维细胞增殖作用。方法:采用[3H ]-TdR掺 入率测定和RT-PCR。结果:醛固酮(1×10-9~1×10-6)mol/L能明 显促进心室 成纤维细胞的[3H]-TdR掺入率,且呈剂量依赖方式;醛固酮孵育15 min,可见c-fos mRNA的表达,至1 h表达达高峰,以后逐渐降低,醛固酮受体拮抗剂螺旋内酯能阻断醛固酮的作 用。结论:醛固酮能促进心室成纤维细胞增殖,是通过其特异性受体介导的 。

  18. Renin and aldosterone measurements in the management of arterial hypertension.

    Science.gov (United States)

    Viola, A; Monticone, S; Burrello, J; Buffolo, F; Lucchiari, M; Rabbia, F; Williams, T A; Veglio, F; Mengozzi, G; Mulatero, P

    2015-06-01

    Renin-angiotensin-aldosterone system (RAAS) is recognized as the main regulatory system of hemodynamics in man, and its derangements have a key role in the development and maintenance of arterial hypertension. Classification of the hypertensive states according to different patterns of renin and aldosterone levels ("RAAS profiling") allows the diagnosis of specific forms of secondary hypertension and may identify distinct hemodynamic subsets in essential hypertension. In this review, we summarize the application of RAAS profiling for the diagnostic assessment of hypertensive patients and discuss how the pathophysiological framework provided by RAAS profiling may guide therapeutic decision-making, especially in the context of uncontrolled hypertension not responding to multi-therapy.

  19. Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone+salt-induced cardiac fibrosis in vivo.

    Science.gov (United States)

    Mummidi, Srinivas; Das, Nitin A; Carpenter, Andrea J; Kandikattu, Hemanthkumar; Krenz, Maike; Siebenlist, Ulrich; Valente, Anthony J; Chandrasekar, Bysani

    2016-09-01

    The overall goals of this study were to investigate whether metformin exerts anti-fibrotic effects in aldosterone (Aldo)+salt-treated wild type mouse hearts, and determine the underlying molecular mechanisms in isolated adult cardiac fibroblasts (CF). In vitro, Aldo induced CF activation, migration, and proliferation, and these effects were inhibited by metformin. Further, Aldo induced PPM1A (Protein Phosphatase Magnesium Dependent 1A) activation and inhibited AMPK phosphorylation. At a pharmacologically relevant concentration, metformin restored AMPK activation, and inhibited Aldo-induced Nox4/H2O2-dependent TRAF3IP2 induction, pro-inflammatory cytokine expression, and CF migration and proliferation. Further, metformin potentiated the inhibitory effects of spironolactone, a mineralocorticoid receptor antagonist, on Aldo-induced collagen expression, and CF migration and proliferation. These results were recapitulated in vivo, where metformin reversed Aldo+salt-induced oxidative stress, suppression of AMPK activation, TRAF3IP2 induction, pro-inflammatory cytokine expression, and cardiac fibrosis, without significantly modulating systolic blood pressure. These in vitro and in vivo data indicate that metformin has the potential to reduce adverse cardiac remodeling in hypertensive heart disease.

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

    NARCIS (Netherlands)

    K. Verdonk (Koen)

    2015-01-01

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

  1. Galectin-3 Mediates Aldosterone-Induced Vascular Fibrosis

    NARCIS (Netherlands)

    Calvier, Laurent; Miana, Maria; Reboul, Pascal; Cachofeiro, Victoria; Martinez-Martinez, Ernesto; de Boer, Rudolf A.; Poirier, Francoise; Lacolley, Patrick; Zannad, Faiez; Rossignol, Patrick; Lopez-Andres, Natalia

    2013-01-01

    Objective-Aldosterone (Aldo) is involved in arterial stiffness and heart failure, but the mechanisms have remained unclear. Galectin-3 (Gal-3), a beta-galactoside-binding lectin, plays an important role in inflammation, fibrosis, and heart failure. We investigated here whether Gal-3 is involved in A

  2. 21 CFR 862.1045 - Aldosterone test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Aldosterone test system. 862.1045 Section 862.1045 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  3. Aldosterone-induced apoptosis of MIN6 cells and its mechanism%醛固酮诱导MIN6细胞凋亡及作用机制研究

    Institute of Scientific and Technical Information of China (English)

    潘瑜; 刘晓莉; 束金莲; 张霞; 金惠敏

    2012-01-01

    Objective To investigate the effects of aldosterone on apoptosis of tnurine pancreatic islets B cell line MIN6, and explore its possible mechanism. Methods Murine pancreatic islets B cell line MIN6 cultured in vitro was divided into control group (treated with serum-free DMEM culture medium), aldosterone group (treated with 10, 100 or 1 000 nmol/L aldosterone) and aldosterone + aldosterone antagonist group ( treated with 100 nmol/L aldosterone and 100 nmol/L aldactone). Cell viability was determined by MTT assay, glucose-stimulated insulin secretion ( GSIS) was measured by radioimmunoassay, cell apoptosis was detected by flow cytometry in combination with FITC-Annexin V/PI fluorescein staining, Caspase-3 activity in supernatant of culture fluid was determined by ELISA, and the expression of apoptosis-related proteins of cytochrome C(Cyt-C), Bcl-2, Bax and phosphorylated protein kinase C ( p-Akt) was detected by Western blotting. Results The viability of MIN6 cells decreased with the increase of concentrations of aldosterone, with a concentration-dependent manner. Under physical glucose concentration (5.6 mmol/L) and high glucose concentration (28 mmol/L) environment, GSIS of aldosterone group was significantly lower than that of control group ( P <0. 01), and GSIS of aldosterone + aldosterone antagonist group was significantly higher than that of aldosterone group ( P < 0. 01). The cell apoptosis ratio of aldosterone group was significantly higher than that of control group ( P <0.01), and the cell apoptosis ratio of aldosterone + aldosterone antagonist group was significantly lower than that of aldosterone group (P < 0. 01). Compared with control group, the Caspase-3 activity and expression of Cyt-C were significantly higher, and Bcl-2/ Bax and the expression of p-Akt were significantly lower ( P < 0. 01 for all), while aldosterone antagonist significantly inhibited aldosterone-mediated Caspase-3 activity increase and abnormal expression of related proteins

  4. [Primary aldosteronism and pregnancy: report of 2 cases].

    Science.gov (United States)

    Germain, Alfredo M; Kottman, Cristián; Valdés, Gloria

    2002-12-01

    Based on two patients, we discuss the difficulties in diagnosing and managing primary aldosteronism in pregnancy, which derive from changes of the renin-angiotensin-aldosterone axis, from the uncertainty regarding blood pressure control along gestation and postpartum, and from the contraindication to the use of spironolactone. The first case is a 27 years old woman with a long standing refractory hypertension, a hemorrhagic stroke with left brachial hemiplegia and crural hemiparesia, two miscarriages, one stillbirth and one offspring with intrauterine growth retardation. Due to hypokalemia, a plasma aldosterone/renin activity ratio of 91, and a negative genetic screening for glucocorticoid remediable aldosteronism (GRA), a primary hyperaldosteronism with normal adrenals in CT scan was diagnosed, and good blood pressure control was attained with spironolactone. After two and a half years of normotension, a fifth pregnancy, managed with methyldopa evolved with satisfactory blood pressures, plasma potassium, fetal growth, uterine and umbilical arterial resistance indexes, and maternal endothelial function. At 37 1/2 weeks of pregnancy the patient delivered a healthy newborn weighing 2,960 g. Blood pressure rose during the 48 hours of postpartum in the absence of proteinuria and required i.v. hydralazine. The second patient is a 37 years old woman, with known refractory hypertension for 7 years, hypokalemia, plasma aldosterone/renin activity ratio greater than 40, normal adrenals in the CAT scan, and a negative genetic screening for GRA. She had normotensive pregnancies 5 and 3 years prior to the detection of hypertension, with hypertensive crisis in both postpartum periods, retrospectively considered as expressions of primary hyperaldosteronism.

  5. Review of Current Research on Aldosterone and Left Ventricular Remodeling after Acute Myocardial Infarction%醛固酮对急性心肌梗死后左心室重构影响的研究进展

    Institute of Scientific and Technical Information of China (English)

    吴春涛

    2011-01-01

    心力衰竭已经成为影响人们生命和生活质量的主要疾病,心肌梗死后心室重构是其重要原因之一,急性心肌梗死后神经内分泌系统的过度激活对心室重构的影响已成为共识.作为肾素-血管紧张素-醛固酮系统的重要组成部分,醛固酮对于心血管系统的病理生理作用以及醛固酮逃逸现象确定了醛固酮受体拮抗剂在心力衰竭治疗中的决定性地位.现就醛固酮对于急性心肌梗死后左心室重构影响的研究进展作一综述.%Heart failure is a disease that affects people's quality of life, and ventricular remodeling after myocardial infarction is one of the major reasons. There is a consensus on the effect of over-activation of the neuroendocrine system after acute myocardial infarction ( AMI) on ventricular remodeling. Aldosterone acts as an important part of the renin-angiotensin-aldosterone system, and the aldosterone receptor antagonist plays a crucial role in the modern therapeutic regimen for heart failure attributed to aldosterone's pathophysiological effects on the cardiovascular system and aldosterone escape phenomenon. This article reviews the effects of aldosterone on left ventricular remodeling of AMI.

  6. What is the role of aldosterone excess in resistant hypertension and how should it be investigated and treated?

    Science.gov (United States)

    Sica, Domenic A

    2011-12-01

    Resistant hypertension has evolved as an important global health care problem. Primary aldosteronism is one of several potentially reversible causes of resistant hypertension. Primary aldosteronism can be effectively treated, when recognized, with a mineralocorticoid receptor antagonist, such as spironolactone and eplerenone. Each of these compounds can reduce blood pressure as monotherapy or when given with a range of other antihypertensive drug classes. These compounds have distinctive pharmacokinetic and pharmacodynamic patterns that require some forethought in their use before they are prescribed. However, as the use of mineralocorticoid-blocking agents has gradually increased, the hazards inherent to use of such drugs has become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove fatal if sufficient degrees of hyperkalemia develop. However, for most patients the risk of developing hyperkalemia in and of itself should not discourage the prudent clinician from bringing these compounds into play. Hyperkalemia should always be considered as a likelihood in any patient receiving one or the other of these medications. As such, steps should be taken to lessen the likelihood of it occurring if therapy is being contemplated with agents in this class.

  7. Type I receptors in parotid, colon, and pituitary are aldosterone selective in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Sheppard, K.; Funder, J.W. (Prince Henry' s Hospital, Melbourne (Australia))

    1987-10-01

    Previous in vivo studies have demonstrated that type I receptors in the rat kidney are aldosterone selective, whereas those in the hippocampus do not appear to discriminate between aldosterone and corticosterone. The authors have injected mature rats with ({sup 3}H)aldosterone or ({sup 3}H)corticosterone plus 100-fold excess of RU 28362, with or without unlabeled aldosterone or corticosterone, and compared type I receptor occupancy in two classic mineralocorticoid target tissues (parotid and colon) and in the pituitary. Mature rats were killed 10-180 min after tracer administration; ({sup 3}H)aldosterone was well taken up and retained in all tissues, whereas ({sup 3}H)corticosterone was significantly retained only in the pituitary 10 min after tracer administration. To assess a possible role for corticosterone-binding globulin (CBG) in conferring aldosterone specificity on type I receptors, 10-day-old rats (with very low levels of CBG) were similarly injected. In the colon and parotid, ({sup 3}H)aldosterone binding was at least an order of magnitude higher than that of corticosterone; in the pituitary aldosterone binding was approximately three times that of corticosterone. They interpret these data as evidence that in the parotid and colon type I receptors are aldosterone selective by a non-CBG-requiring mechanism, whereas in the pituitary there appear to be both aldosterone-selective and nonselective type I sites.

  8. Aldosterone induced galectin-3 secretion in vitro and in vivo: from cells to humans.

    Directory of Open Access Journals (Sweden)

    Yen-Hung Lin

    Full Text Available Patients with primary aldosteronism are associated with increased myocardial fibrosis. Galectin-3 is one of the most important mediators between macrophage activation and myocardial fibrosis.To investigate whether aldosterone induces galectin-3 secretion in vitro and in vivo.We investigated the possible molecular mechanism of aldosterone-induced galectin-3 secretion in macrophage cell lines (THP-1 and RAW 264.7 cells. Aldosterone induced galectin-3 secretion through mineralocorticoid receptors via the PI3K/Akt and NF-κB transcription signaling pathways. In addition, aldosterone-induced galectin-3 expression enhanced fibrosis-related factor expression in fibroblasts. We observed that galectin-3 mRNA from peripheral blood mononuclear cells and serum galectin-3 levels were both significantly increased in mice implanted with aldosterone pellets on days 7 and 14. We then conducted a prospective preliminary clinical study to investigate the association between aldosterone and galectin-3. Patients with aldosterone-producing adenoma had a significantly higher plasma galectin-3 level than patients with essential hypertension. One year after adrenalectomy, the plasma galectin-3 level had decreased significantly in the patients with aldosterone-producing adenoma.This study demonstrated that aldosterone could induce galectin-3 secretion in vitro and in vivo.

  9. Association of restriction fragment length polymorphism at the atrial natriuretic peptide gene locus with aldosterone responsiveness to angiotensin in aldosterone-producing adenoma.

    Science.gov (United States)

    Tunny, T J; Jonsson, J R; Klemm, S A; Ballantine, D M; Stowasser, M; Gordon, R D

    1994-11-15

    Primary aldosteronism is an important, potentially curable, form of hypertension. We examined the possible association between restriction fragment length polymorphisms in the atrial natriuretic peptide (ANP) gene and responsiveness of aldosterone to angiotensin II in 59 patients with primary aldosteronism due to aldosterone-producing adenoma (APA). Significant differences in the allelic frequencies of the BglI, TaqI and XhoI polymorphic sites at the ANP gene locus (chromosome 1; 1p36) between angiotensin II-unresponsive and angiotensin II-responsive tumors were observed. Variation in the ANP gene between the two groups may result in altered expression of ANP within the adrenal gland, and may contribute to the biochemical regulation of aldosterone production of these two subgroups of patients with APA.

  10. Microalbuminuria and hypertension in pregnancy: role of aldosterone and inflammation.

    Science.gov (United States)

    Armanini, Decio; Ambrosini, Guido; Sabbadin, Chiara; Donà, Gabriella; Clari, Giulio; Bordin, Luciana

    2013-09-01

    Women with a history of hypertension in pregnancy are at increased risk of microalbuminuria later in life. Microalbuminuria is a marker of kidney dysfunction frequently related to an inflammatory event. Pregnancy is a dynamic process characterized by immune tolerance, angiogenesis, and hormonal regulation. Menstruation and pregnancy are associated with a physiological inflammation, which is altered in preeclampsia and probably in other hypertensive situations of pregnancy. An imbalance between pro-oxidant factors and the ability to scavenge these factors produces oxidative stress, which has been evaluated in many cells, but leukocytes are the main source of inflammatory cytokines and experimental and clinical evidence support a possible role of aldosterone as a mediator of placental and renal damage mediated by growth factors, reactive oxygen species, and cytokines. Angiotensin-converting enzyme inhibitors and aldosterone receptor blockers are frequently effective in reducing the risk of progression of cardiovascular and renal disease.

  11. High prevalence of thyroid ultrasonographic abnormalities in primary aldosteronism.

    Science.gov (United States)

    Armanini, Decio; Nacamulli, Davide; Scaroni, Carla; Lumachi, Franco; Selice, Riccardo; Fiore, Cristina; Favia, Gennaro; Mantero, Franco

    2003-11-01

    The study was performed to evaluate the prevalence of thyroid abnormalities detected by ultrasonography and, in particular, of multinodular nontoxic goiter in primary aldosteronism. We analyzed 80 consecutive of patients with primary hyperaldosteronism (40 with unilateral adenoma and 40 with idiopathic hyperaldosteronism) and 80 normotensive healthy controls, comparable for age, sex, iodine intake, and geographical area. Blood pressure, thyroid palpation, thyroid function, and ultrasonography were evaluated. The prevalence of ultrasonographic thyroid abnormalities was 60% in primary aldosteronism and 27% in controls (p < 0.0001). There was a statistically significant difference in prevalence of these abnormalities in unilateral adenoma and idiopathic hyperaldosteronism with respect to controls (p < 0.05 and p < 0.0001, respectively). The prevalence of multinodular nontoxic goiter in idiopathic hyperaldosteronism was higher than in controls (p < 0.001) and, in particular, in female patients. From these data it seems to be worth considering the existence of primary hyperaldosteronism in patients with multinodular goiter and hypertension.

  12. Zero gravity and cardiovascular homeostasis. The relationship between endogenous hyperprolactinemia and plasma aldosterone

    Science.gov (United States)

    Haber, E.; Re, R. N.; Kourides, I. A.; Weihl, A. C.; Maloof, F.

    1978-01-01

    Prolactin, thyrotropin and aldosterone were measured by radioimmunoassay and plasma renin activity by the radioimmunoassay of angiotensin I in normal women before and after the intravenous injection of 200 micrograms of thyrotropin releasing hormone. Prolactin increased at 15 minutes following thyrotropin releasing hormone. Plasma renin activity was not different from control levels during the first hour following the administration of thyrotropin releasing hormone, nor did the plasma aldosterone concentration differ significantly from the control levels during this period. However, with upright posture, an increase in aldosterone and in plasma renin activity was noted, demonstrating a normal capacity to secrete aldosterone. Similarly, no change in aldosterone was seen in 9 patients with primary hypothyroidism given thyrotropin releasing hormone, despite the fact that the increase in prolactin was greater than normal. These data demonstrate that acutely or chronically elevated serum prolactin levels do not result in increased plasma aldosterone levels in humans.

  13. Does aldosterone play a significant role for regulation of vascular tone?

    DEFF Research Database (Denmark)

    Lyngsø, Kristina Sanne; Assersen, Kasper Bostlund; Dalgaard, Emil Geertsen;

    2016-01-01

    Besides the well-known renal effects of aldosterone, the hormone is now known to have direct vascular effects. Clinical observations underline substantial adverse effects of aldosterone on cardiovascular function. The source of systemic circulating aldosterone is the adrenal gland zona glomerulosa...... cells through stimulus-secretion coupling involving depolarization, opening of L- and T-type calcium channels and aldosterone synthase activation. Local formation and release in peripheral tissues such as perivascular fat is recognized. Where does aldosterone affect the vasculature? Mineralocorticoid...... receptors (MR) are present in endothelial and vascular smooth muscle cells and MR-independent pathways are also involved. The vascular effects of aldosterone are complex, both concentration, temporal and spatial aspects are relevant. The acute response includes vasodilation through endothelial nitric oxide...

  14. Physiological techniques in the study of rapid aldosterone effects.

    Science.gov (United States)

    Yusef, Yamil R; Thomas, Warren; Harvey, Brian J

    2014-01-01

    Molecular imaging and electrophysiological techniques are powerful tools to analyze the responses stimulated by aldosterone and other hormones in target tissues. Studies with Ussing-type chambers can be used to measure and characterize changes in transepithelial currents resulting from hormone treatment. Confocal imaging techniques can be used in real time or in fixed preparations to evaluate the localization of receptors, signalling intermediates, and transporters.

  15. Ceramide Production Mediates Aldosterone-Induced Human Umbilical Vein Endothelial Cell (HUVEC) Damages.

    Science.gov (United States)

    Zhang, Yumei; Pan, Yu; Bian, Zhixiang; Chen, Peihua; Zhu, Shijian; Gu, Huiyi; Guo, Liping; Hu, Chun

    2016-01-01

    Here, we studied the underlying mechanism of aldosterone (Aldo)-induced vascular endothelial cell damages by focusing on ceramide. We confirmed that Aldo (at nmol/L) inhibited human umbilical vein endothelial cells (HUVEC) survival, and induced considerable cell apoptosis. We propose that ceramide (mainly C18) production might be responsible for Aldo-mediated damages in HUVECs. Sphingosine-1-phosphate (S1P), an anti-ceramide lipid, attenuated Aldo-induced ceramide production and following HUVEC damages. On the other hand, the glucosylceramide synthase (GCS) inhibitor PDMP or the ceramide (C6) potentiated Aldo-induced HUVEC apoptosis. Eplerenone, a mineralocorticoid receptor (MR) antagonist, almost completely blocked Aldo-induced C18 ceramide production and HUVEC damages. Molecularly, ceramide synthase 1 (CerS-1) is required for C18 ceramide production by Aldo. Knockdown of CerS-1 by targeted-shRNA inhibited Aldo-induced C18 ceramide production, and protected HUVECs from Aldo. Reversely, CerS-1 overexpression facilitated Aldo-induced C18 ceramide production, and potentiated HUVEC damages. Together, these results suggest that C18 ceramide production mediates Aldo-mediated HUVEC damages. MR and CerS-1 could be the two signaling molecule regulating C18 ceramide production by Aldo.

  16. Ceramide Production Mediates Aldosterone-Induced Human Umbilical Vein Endothelial Cell (HUVEC Damages.

    Directory of Open Access Journals (Sweden)

    Yumei Zhang

    Full Text Available Here, we studied the underlying mechanism of aldosterone (Aldo-induced vascular endothelial cell damages by focusing on ceramide. We confirmed that Aldo (at nmol/L inhibited human umbilical vein endothelial cells (HUVEC survival, and induced considerable cell apoptosis. We propose that ceramide (mainly C18 production might be responsible for Aldo-mediated damages in HUVECs. Sphingosine-1-phosphate (S1P, an anti-ceramide lipid, attenuated Aldo-induced ceramide production and following HUVEC damages. On the other hand, the glucosylceramide synthase (GCS inhibitor PDMP or the ceramide (C6 potentiated Aldo-induced HUVEC apoptosis. Eplerenone, a mineralocorticoid receptor (MR antagonist, almost completely blocked Aldo-induced C18 ceramide production and HUVEC damages. Molecularly, ceramide synthase 1 (CerS-1 is required for C18 ceramide production by Aldo. Knockdown of CerS-1 by targeted-shRNA inhibited Aldo-induced C18 ceramide production, and protected HUVECs from Aldo. Reversely, CerS-1 overexpression facilitated Aldo-induced C18 ceramide production, and potentiated HUVEC damages. Together, these results suggest that C18 ceramide production mediates Aldo-mediated HUVEC damages. MR and CerS-1 could be the two signaling molecule regulating C18 ceramide production by Aldo.

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

    Directory of Open Access Journals (Sweden)

    V. I. Podzolkov

    2010-01-01

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

  18. Malignant hypertension and hypertensive encephalopathy in primary aldosteronism caused by adrenal adenoma

    Directory of Open Access Journals (Sweden)

    Bortolotto Luiz Aparecido

    2003-01-01

    Full Text Available Two cases are reported as follows: 1 1 female patient with accelerated-malignant hypertension secondary to an aldosterone-producing adrenal adenoma; and 2 1 female patient with adrenal adenoma, severe hypertension, and hypertensive encephalopathy. This association is a rare clinical finding, and malignant hypertension may modify the hormonal characteristic of primary aldosteronism, making its diagnosis more difficult. The diagnosis of primary aldosteronism should be considered in patients with malignant hypertension or hypertensive encephalopathy if persistent hypokalemia occurs. Identification of primary aldosteronism is of paramount importance for the patient's evolution, because the surgical treatment makes the prognosis more favorable.

  19. Aldosterone-induced signalling and cation transport in the distal nephron.

    LENUS (Irish Health Repository)

    Thomas, Warren

    2008-10-01

    Aldosterone is an important regulator of Na(+) and K(+) transport in the distal nephron modulating the surface expression of transporters through the action of the mineralocorticoid receptor as a ligand-dependent transcription factor. Aldosterone stimulates the rapid activation of protein kinase-based signalling cascades that modulate the genomic effects of the hormone. Evidence is accumulating about the multi-factorial regulation of the epithelial sodium channel (ENaC) by aldosterone. Recent published data suggests that the activation of a novel PKC\\/PKD signalling pathway through the c-Src-dependent trans-activation of epidermal growth factor receptor contributes to early ENaC trafficking in response to aldosterone.

  20. The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy.

    Science.gov (United States)

    Sato, Atsuhisa

    2015-06-01

    Diabetes mellitus is a major cause of chronic kidney disease (CKD), and diabetic nephropathy is the most common primary disease necessitating dialysis treatment in the world including Japan. Major guidelines for treatment of hypertension in Japan, the United States and Europe recommend the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, which suppress the renin-angiotensin system (RAS), as the antihypertensive drugs of first choice in patients with coexisting diabetes. However, even with the administration of RAS inhibitors, failure to achieve adequate anti-albuminuric, renoprotective effects and a reduction in cardiovascular events has also been reported. Inadequate blockade of aldosterone may be one of the reasons why long-term administration of RAS inhibitors may not be sufficiently effective in patients with diabetic nephropathy. This review focuses on treatment in diabetic nephropathy and discusses the significance of aldosterone blockade. In pre-nephropathy without overt nephropathy, a mineralocorticoid receptor antagonist can be used to enhance the blood pressure-lowering effects of RAS inhibitors, improve insulin resistance and prevent clinical progression of nephropathy. In CKD categories A2 and A3, the addition of a mineralocorticoid receptor antagonist to an RAS inhibitor can help to maintain 'long-term' antiproteinuric and anti-albuminuric effects. However, in category G3a and higher, sufficient attention must be paid to hyperkalemia. Mineralocorticoid receptor antagonists are not currently recommended as standard treatment in diabetic nephropathy. However, many studies have shown promise of better renoprotective effects if mineralocorticoid receptor antagonists are appropriately used.

  1. The renal thiazide-sensitive Na-Cl cotransporter as mediator of the aldosterone-escape phenomenon

    OpenAIRE

    Wang, Xiao-Yan; Masilamani, Shyama; Nielsen, Jakob; Kwon, Tae-Hwan; Brooks, Heddwen L.; Nielsen, Søren; Knepper, Mark A.

    2001-01-01

    The kidneys “escape” from the Na-retaining effects of aldosterone when circulating levels of aldosterone are inappropriately elevated in the setting of normal or expanded extracellular fluid volume, e.g., in primary aldosteronism. Using a targeted proteomics approach, we screened renal protein extracts with rabbit polyclonal antibodies directed to each of the major Na transporters expressed along the nephron to determine whether escape from aldosterone-mediated Na retention is associated with...

  2. Higher serum aldosterone correlates with lower hearing thresholds: a possible protective hormone against presbycusis.

    Science.gov (United States)

    Tadros, Sherif F; Frisina, Susan T; Mapes, Frances; Frisina, D Robert; Frisina, Robert D

    2005-11-01

    Aldosterone hormone is a mineralocorticoid secreted by adrenal gland cortex and controls serum sodium (Na(+)) and potassium (K(+)) levels. Aldosterone has a stimulatory effect on expression of sodium-potassium ATPase (Na, K-ATPase) and sodium-potassium-chloride cotransporter (NKCC) in cell membranes. In the present investigation, the relation between serum aldosterone levels and age-related hearing loss (presbycusis) and the correlation between these levels versus the degree of presbycusis in humans were examined. Serum aldosterone concentrations were compared between normal hearing and presbycusic groups. Pure-tone audiometry, transient evoked otoacoustic emissions (TEOAE), hearing in noise test (HINT) and gap detection were tested for each subject and compared to the serum aldosterone levels. A highly significant difference between groups in serum aldosterone concentrations was found (p = 0.0003, t = 3.95, df = 45). Highly significant correlations between pure-tone thresholds in both right and left ears, and HINT scores versus serum aldosterone levels were also discovered. On the contrary, no significant correlations were seen in the case of TEOAEs and gap detection. We conclude that aldosterone hormone may have a protective effect on hearing in old age. This effect is more peripheral than central, appearing to affect inner hair cells more than outer hair cells.

  3. Non-genomic actions of aldosterone: From receptors and signals to membrane targets.

    LENUS (Irish Health Repository)

    2012-02-01

    In tissues which express the mineralocorticoid receptor (MR), aldosterone modulates the expression of membrane targets such as the subunits of the epithelial Na(+) channel, in combination with important signalling intermediates such as serum and glucocorticoid-regulated kinase-1. In addition, the rapid \\'non-genomic\\' activation of protein kinases and secondary messenger signalling cascades has also been detected in aldosterone-sensitive tissues of the nephron, distal colon and cardiovascular system. These rapid actions are variously described as being coupled to MR or to an as yet unidentified, membrane-associated aldosterone receptor. The rapidly activated signalling cascades add a level of fine-tuning to the activity of aldosterone-responsive membrane transporters and also modulate the aldosterone-induced changes in gene expression through receptor and transcription factor phosphorylation.

  4. Non-genomic actions of aldosterone: From receptors and signals to membrane targets.

    LENUS (Irish Health Repository)

    Dooley, Ruth

    2011-07-26

    In tissues which express the mineralocorticoid receptor (MR), aldosterone modulates the expression of membrane targets such as the subunits of the epithelial Na(+) channel, in combination with important signalling intermediates such as serum and glucocorticoid-regulated kinase-1. In addition, the rapid \\'non-genomic\\' activation of protein kinases and secondary messenger signalling cascades has also been detected in aldosterone-sensitive tissues of the nephron, distal colon and cardiovascular system. These rapid actions are variously described as being coupled to MR or to an as yet unidentified, membrane-associated aldosterone receptor. The rapidly activated signalling cascades add a level of fine-tuning to the activity of aldosterone-responsive membrane transporters and also modulate the aldosterone-induced changes in gene expression through receptor and transcription factor phosphorylation.

  5. Rapid actions of aldosterone in vascular health and disease - friend or foe?

    DEFF Research Database (Denmark)

    Skøtt, Ole; Uhrenholt, Torben Rene; Schjerning, Jeppe;

    2006-01-01

    The mineralocorticoid receptor (MR) and the enzyme 11betahydroxysteroid dehydrogenase type 2, which confers aldosterone specificity to the MR, are present in endothelium and vascular smooth muscle. In several pathological conditions aldosterone promotes vascular damage by formation of reactive...... oxygen species. The effect of aldosterone on vascular function, however, is far from clear. By rapid non-genomic mechanisms aldosterone may cause calcium mobilization and vasoconstriction, or may stimulate nitric oxide formation through the PI-3 kinase/Akt pathway and thereby counteract vasoconstriction....... Vasoconstrictor, vasodilator or no effects of aldosterone have been reported from studies on human forearm blood flow. Inhibition of MR with spironolactone improves endothelial function in patients with heart failure but worsens endothelial function in type 2 diabetic patients. The aim of the present review...

  6. Localization of aldosterone-producing adenoma on computed tomography. A comparative study with adrenal scintigraphy and plasma aldosterone concentration in the adrenal or renal vein

    Energy Technology Data Exchange (ETDEWEB)

    Haruyama, K.; Shigetomi, S.; Yamazaki, M.; Toki, T.; Yaginuma, K.; Fukuchi, S. (Fukushima Medical Coll. (Japan))

    1982-09-01

    An abdominal CT scan was performed on six patients with primary aldosteronism, one with idiopathic hyperaldosteronism and one with glucocorticoid responsive hyperaldosteronism; in an attempt to evaluate the utility of this noninvasive procedure. Diagnosis of hyperaldosteronism was made by demonstrating the elevated plasma aldosterone concentration and aldosterone secretion rate, normal excretion rate of urinary 17-OHCS and 17-KS, and low plasma renin activity. The CT scan correctly predicted unilateral adrenal adenoma in all the patients with primary aldosteronism of which the findings were identical to those demonstrated by surgery. The diameter of these tumors ranged from 10 x 7 x 6 to 19 x 17 x 14 mm. Also the CT scan in idiopathic hyperaldosteronism and glucocorticoid responsive hyperaldosteronism showed bilateral adrenal hyperplasia and bilateral normal adrenal glands, respectively. The pathological findings in these two cases disclosed the adrenal hyperplasia of zona glomerulosa and adrenal hyperplasia of zona subglomerulosa accompanied by a normal thickness of the adrenal gland, respectively. The precision of the CT scan, adrenal scintigraphy and determination of plasma aldosterone in the adrenal or renal veins were almost equal to the diagnosis of the localization of adrenal adenoma. It is concluded that the CT scan is a noninvasive and most useful method for the localization of aldosterone-producing adenoma and helpful in distinguishing adrenal adenoma from adrenal hyperplasia.

  7. Diagnostic value of plasma aldosterone/potassium ratio in hypoaldosteronism.

    Science.gov (United States)

    Shiah, C J; Wu, K D; Tsai, D M; Liao, S T; Siauw, C P; Lee, L S

    1995-05-01

    The diagnosis of hypoaldosteronism usually depends upon a combination of abnormal clinical and laboratory findings. The most common abnormality in hypoaldosteronism is hyperkalemia, which may be combined with sodium depletion. In the present study, 5 of 16 patients diagnosed with isolated hypoaldosteronism (IHA) had sodium depletion due to renal salt wasting, and four patients had normokalemia. Of these 16 IHA patients, 70% had subnormal baseline and stimulated plasma renin activity (PRA). Six patients diagnosed with type I pseudohypoaldosteronism (PHA) had normal or high PRA and plasma aldosterone concentrations (PAC). In 11 control subjects, supine PAC correlated positively with serum potassium (SK), and PAC stimulated by furosemide and ambulation correlated with the 24-hour urinary potassium excretion (UK). However, these correlations were not found in IHA and PHA patients. The ratio of UK/UNa+K and UNa/UK correlated with the stimulated PAC when the IHA and control subjects were taken as a whole. However, these electrolyte excretion parameters bore no relationship to the supine PAC. The stimulated PAC/SK ratio was used to discriminate the three groups; all IHA patients had a ratio below 3. The results indicate that stimulated PAC reflects the bioactivity of aldosterone on the collecting tubule, and the stimulated PAC/SK ratio is useful for the diagnosis of hypoaldosteronism and pseudohypoaldosteronism.

  8. Long-term aldosterone treatment induces decreased apical but increased basolateral expression of AQP2 in CCD of rat kidney

    DEFF Research Database (Denmark)

    de Seigneux, Sophie; Nielsen, Jakob; Olesen, Emma T B;

    2007-01-01

    of hypokalemia in aldosterone-treated rats, we studied dietary-induced hypokalemia in rats, which also reduced apical AQP2 expression in the CCD but did not induce any increase in basolateral AQP2 expression in the CCD as observed with aldosterone treatment. The aldosterone-induced basolateral AQP2 expression...... in the CCD was thus independent of hypokalemia but was dependent on the presence of sodium and aldosterone. This redistribution was clearly blocked by mineralocorticoid receptor blockade. The increased basolateral expression of AQP2 induced by aldosterone may play a significant role in water metabolism...... in conditions with increased sodium reabsorption in the CCD....

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

    Science.gov (United States)

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

    2012-01-01

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

  10. Interleukin-18 deficiency protects against renal interstitial fibrosis in aldosterone/salt-treated mice.

    Science.gov (United States)

    Tanino, Akiko; Okura, Takafumi; Nagao, Tomoaki; Kukida, Masayoshi; Pei, Zuowei; Enomoto, Daijiro; Miyoshi, Ken-Ichi; Okamura, Haruki; Higaki, Jitsuo

    2016-10-01

    Interleukin (IL)-18 is a member of the IL-1 family of cytokines and was described originally as an interferon γ-inducing factor. Aldosterone plays a central role in the regulation of sodium and potassium homoeostasis by binding to the mineralocorticoid receptor and contributes to kidney and cardiovascular damage. Aldosterone has been reported to induce IL-18, resulting in cardiac fibrosis with induced IL-18-mediated osteopontin (OPN). We therefore hypothesized that aldosterone-induced renal fibrosis via OPN may be mediated by IL-18. To verify this hypothesis, we compared mice deficient in IL-18 and wild-type (WT) mice in a model of aldosterone/salt-induced hypertension. IL-18(-/-) and C57BL/6 WT mice were used for the uninephrectomized aldosterone/salt hypertensive model, whereas NRK-52E cells (rat kidney epithelial cells) were used in an in vitro model. In the present in vivo study, IL-18 protein expression was localized in medullary tubules in the WT mice, whereas in aldosterone-infused WT mice this expression was up-regulated markedly in the proximal tubules, especially in injured and dilated tubules. This renal damage caused by aldosterone was attenuated significantly by IL-18 knockout with down-regulation of OPN expression. In the present in vitro study, aldosterone directly induced IL-18 gene expression in renal tubular epithelial cells in a concentration- and time-dependent manner. These effects were inhibited completely by spironolactone. IL-18 may be a key mediator of aldosterone-induced renal fibrosis by inducing OPN, thereby exacerbating renal interstitial fibrosis. Inhibition of IL-18 may therefore provide a potential target for therapeutic intervention aimed at preventing the progression of renal injury.

  11. Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors.

    Science.gov (United States)

    Nagase, Miki; Yoshida, Shigetaka; Shibata, Shigeru; Nagase, Takashi; Gotoda, Takanari; Ando, Katsuyuki; Fujita, Toshiro

    2006-12-01

    Metabolic syndrome is an important risk factor for proteinuria and chronic kidney disease independent of diabetes and hypertension; however, the underlying mechanisms have not been elucidated. Aldosterone is implicated in target organ injury of obesity-related disorders. This study investigated the role of aldosterone in the early nephropathy of 17-wk-old SHR/NDmcr-cp, a rat model of metabolic syndrome. Proteinuria was prominent in SHR/NDmcr-cp compared with nonobese SHR, which was accompanied by podocyte injury as evidenced by foot process effacement, induction of desmin and attenuation of nephrin. Serum aldosterone level, renal and glomerular expressions of aldosterone effector kinase Sgk1, and oxidative stress markers all were elevated in SHR/NDmcr-cp. Mineralocorticoid receptors were expressed in glomerular podocytes. Eplerenone, a selective aldosterone blocker, effectively improved podocyte damage, proteinuria, Sgk1, and oxidant stress. An antioxidant tempol also alleviated podocyte impairment and proteinuria, along with inhibition of Sgk1. As for the mechanisms of aldosterone excess, visceral adipocytes that were isolated from SHR/NDmcr-cp secreted substances that stimulate aldosterone production in adrenocortical cells. The aldosterone-releasing activity of adipocytes was not inhibited by candesartan. Adipocytes from nonobese SHR did not show such activity. In conclusion, SHR/NDmcr-cp exhibit enhanced aldosterone signaling, podocyte injury, and proteinuria, which are ameliorated by eplerenone or tempol. The data also suggest that adipocyte-derived factors other than angiotensin II might contribute to the aldosterone excess of this model.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1983-02-01

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

  13. A case of primary aldosteronism combined with acquired nephrogenic diabetes insipidus

    Directory of Open Access Journals (Sweden)

    Kitae Kim

    2014-12-01

    Full Text Available Aldosterone-producing adrenal adenoma can induce various clinical manifestations as a result of chronic exposure to aldosterone. We report a rare case of a 37-year-old man who complained of general weakness and polyuria. He was diagnosed with aldosterone-producing adrenal adenoma and nephrogenic diabetes insipidus. Aldosterone enhances the secretion of potassium in the collecting duct, which can lead to hypokalemia. By contrast, nephrogenic diabetes insipidus, which manifests as polyuria and polydipsia, can occur in several clinical conditions such as acquired tubular disease and those attributed to toxins and congenital causes. Among them, hypokalemia can also damage tubular structures in response to vasopressin. The patient’s urine output was >3 L/d and was diluted. Owing to the ineffectiveness of vasopressin, we eventually made a diagnosis of nephrogenic diabetes insipidus. Laparoscopic adrenalectomy and intraoperative kidney biopsy were subsequently performed. The pathologic finding of kidney biopsy revealed a decrease in aquaporin-2 on immunohistochemical stain.

  14. Cardiac Hypertrophy and Fibrosis in the Metabolic Syndrome: A Role for Aldosterone and the Mineralocorticoid Receptor

    Directory of Open Access Journals (Sweden)

    Eric E. Essick

    2011-01-01

    Full Text Available Obesity and hypertension, major risk factors for the metabolic syndrome, render individuals susceptible to an increased risk of cardiovascular complications, such as adverse cardiac remodeling and heart failure. There has been much investigation into the role that an increase in the renin-angiotensin-aldosterone system (RAAS plays in the pathogenesis of metabolic syndrome and in particular, how aldosterone mediates left ventricular hypertrophy and increased cardiac fibrosis via its interaction with the mineralocorticoid receptor (MR. Here, we review the pertinent findings that link obesity with elevated aldosterone and the development of cardiac hypertrophy and fibrosis associated with the metabolic syndrome. These studies illustrate a complex cross-talk between adipose tissue, the heart, and the adrenal cortex. Furthermore, we discuss findings from our laboratory that suggest that cardiac hypertrophy and fibrosis in the metabolic syndrome may involve cross-talk between aldosterone and adipokines (such as adiponectin.

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

    Energy Technology Data Exchange (ETDEWEB)

    Ceremuzynski, L.K.; Klos, J.; Barcikowski, B.; Herbaczynska-Cedro, K. (Department of Cardiology, Postgraduate Medical School, Warsaw (Poland))

    1991-06-01

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

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

    Science.gov (United States)

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

    2007-04-01

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

  17. Severe hypokalemia-associated rhabdomyolise and unusual poliuria in patient with primary aldosteronism: A case presentation

    OpenAIRE

    Demir, Kenan; Sönmez, Osman; Kayrak, Mehmet; Özdemir, Kurtuluş

    2015-01-01

    Primary aldosteronism is a syndrome that is characterized with hypertension, hypopotasemia, high level of plasma aldosterone, and low plasma renin activity. The case we present is a 56-year-old male who referred to our neurology clinic with proximal muscle weakness and fatigue. Because of uncontrolled blood pressure, a cardiology consultation was performed for the planning of antihypertensive treatment. As prolonged QT intervals and giant U waves due to serious hypokalemia (K+:1,04), cardiolo...

  18. Aldosterone and cortisol co-secreting bifunctional adrenal cortical carcinoma: A rare event

    OpenAIRE

    Chowdhury, Puskar Shyam; Nayak, Prasant; Gurumurthy, Srinivasan; David, Deepak

    2014-01-01

    Adrenocortical carcinoma (ACC) co-secreting aldosterone and cortisol is extremely rare. We report the case of a 37-yearold female who presented with paresis and facial puffiness. Evaluation revealed hypertension, hyperglycemia, severe hypokalemia and hyperaldosteronemia with elevated plasma aldosterone to renin ratio (ARR). Urinary free cortisol estimation showed elevated levels. Computed tomography scan revealed a right adrenal mass. Radical adrenalectomy specimen revealed ACC (T3N1). Post-o...

  19. VLDL-activated cell signaling pathways that stimulate adrenal cell aldosterone production.

    Science.gov (United States)

    Tsai, Ying-Ying; Rainey, William E; Johnson, Maribeth H; Bollag, Wendy B

    2016-09-15

    Aldosterone plays an important role in regulating ion and fluid homeostasis and thus blood pressure, and hyperaldosteronism results in hypertension. Hypertension is also observed with obesity, which is associated with additional health risks, including cardiovascular disease. Obese individuals have high serum levels of very low-density lipoprotein (VLDL), which has been shown to stimulate aldosterone production; however, the mechanisms underlying VLDL-induced aldosterone production are still unclear. Here we demonstrate in human adrenocortical carcinoma (HAC15) cells that submaximal concentrations of angiotensin II and VLDL stimulate aldosterone production in an additive fashion, suggesting the possibility of common mechanisms of action. We show using inhibitors that VLDL-induced aldosterone production is mediated by the PLC/IP3/PKC signaling pathway. Our results suggest that PKC is upstream of the extracellular signal-regulated kinase (ERK) activation previously observed with VLDL. An understanding of the mechanisms mediating VLDL-induced aldosterone production may provide insights into therapies to treat obesity-associated hypertension.

  20. Acute effects of digoxin on plasma aldosterone and cortisol in monkeys.

    Science.gov (United States)

    Kau, Mei-Mei; Kan, Shu-Fen; Wang, Jiing-Rong; Wang, Paulus S; Lau, Ying-Tung; Wang, Shyi-Wu

    2009-01-01

    Digoxin, a cardiac glycoside, is used to increase cardiac contractility via inhibition of Na(+)/K(+)-adenosinetriphosphatase (ATPase) and increase intracellular calcium in congestive heart failure. Inhibitory effects of digoxin have been demonstrated on the biosynthesis of gonadal hormones and adrenal glucocorticoids in rats. However, acute effects of digoxin on levels of adrenal corticosteroid hormones in the primates in vivo are uncertain. Therefore, we test the hypothesis that a single injection of digoxin decreases the secretion of aldosterone and cortisol in monkeys. An intravenous injection of digoxin (1 microg/kg) inhibited basal and adrenocorticotropin (ACTH)- or KCl-stimulated aldosterone release in monkeys. Furthermore, digoxin induced a decrease in ACTH- and KCl-stimulated cortisol release. Administration of digoxin did not alter plasma concentrations of Na(+) and K(+). Ouabain, a selective inhibitor of Na(+)/K(+)-ATPase, did not affect ACTH- or KCl-stimulated aldosterone and cortisol release. These results revealed that injection of digoxin induced an inhibitory effect on aldosterone and cortisol secretion in monkeys. Because ouabain did not affect levels of plasma aldosterone or cortisol, we suggest that (1) the Na(+)/K(+)-ATPase pathway may not be involved in the mechanism of action of digoxin on aldosterone or cortisol secretion in monkeys and/or (2) the Na(+)/K(+)-ATPase is more sensitive to digoxin than to ouabain in monkeys.

  1. Effectiveness of the aldosterone-sodium and -potassium feedback control system.

    Science.gov (United States)

    Young, D B; McCaa, R E; Pan, U J; Guyton, A C

    1976-09-01

    This study was conducted to determine the quantitative importance of the aldosterone feedback mechanism in controlling each one of three major factors that have often been associated with aldosterone, namely, extracellular fluid sodium concentration, extracellular fluid potassium concentration, and extracellular fluid volume. To do this, the ability of the body to control these three factors in the face of marked changes in daily sodium or potassium intake was studied under two conditions: 1) in the normal dog, and 2) in the dog in which the aldosterone feedback mechanism was prevented from functioning by removing the adrenal glands and then providing a continuous fixed level of supportive aldosterone and glucocorticoids during the low and high electrolyte intake periods. Under these conditions, removal of feedback control of aldosterone secretion decreased the effectiveness of plasma potassium control by nearly fivefold (39% vs. 8% change in plasma potassium concentration), fluid volume by sixfold (12% vs. 2% change in sodium space) and had no effect on control of plasma sodium concentration (2% change with and without feedback control of aldosterone secretion.)

  2. Opioid Antagonist Impedes Exposure.

    Science.gov (United States)

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

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

    Science.gov (United States)

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

    2012-11-15

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

  4. Aldosterone status associates with insulin resistance in patients with heart failure-data from the ALOFT study

    OpenAIRE

    Freel, E M; Tsorlalis, I.K.; Lewsey, J D; Latini, R; Maggioni, A.P.; Solomon, S.; Pitt, B; Connell, J M C; McMurray, J.J.V.

    2009-01-01

    Background: Aldosterone plays a key role in the pathophysiology of heart failure. In around 50% of such patients, aldosterone 'escapes' from inhibition by drugs that interrupt the renin-angiotensin axis; such patients have a worse clinical outcome. Insulin resistance is a risk factor in heart failure and cardiovascular disease. The relationship between aldosterone status and insulin sensitivity was investigated in a cohort of heart failure patients.\\ud \\ud Methods: 302 patients with New York ...

  5. Changes in serum aldosterone are associated with changes in obesity-related factors in normotensive overweight and obese young adults

    OpenAIRE

    2013-01-01

    Recent data suggest excess circulating aldosterone promotes cardiometabolic decline. Weight loss may lower aldosterone levels, but little longitudinal data is available in normotensive adults. We aimed to determine if, independent of changes in sodium excretion, reductions in serum aldosterone are associated with favorable changes in obesity-related factors in normotensive overweight/obese young adults. We studied 285 overweight/obese young adult participants (body mass index (BMI) ≥ 25 and <...

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

    Directory of Open Access Journals (Sweden)

    Heleniak Zbigniew

    2016-12-01

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

  7. Drug therapy of apparent treatment-resistant hypertension: focus on mineralocorticoid receptor antagonists.

    Science.gov (United States)

    Glicklich, Daniel; Frishman, William H

    2015-04-01

    Apparent treatment-resistant hypertension (aTRH) is defined as blood pressure (BP) >140/90 mmHg despite three different antihypertensive drugs including a diuretic. aTRH is associated with an increased risk of cardiovascular events, including stroke, chronic renal failure, myocardial infarction, congestive heart failure, aortic aneurysm, atrial fibrillation, and sudden death. Preliminary studies of renal nerve ablation as a therapy to control aTRH were encouraging. However, these results were not confirmed by the Symplicity 3 trial. Therefore, attention has refocused on drug therapy. Secondary forms of hypertension and associated conditions such as obesity, sleep apnea, and primary aldosteronism are common in patients with aTRH. The pivotal role of aldosterone in the pathogenesis of aTRH in many cases is well recognized. For patients with aTRH, the Joint National Committee-8, the European Society of Hypertension, and a recent consensus conference recommend that a diuretic, ACE inhibitor, or angiotensin receptor blocker and calcium channel blocker combination be used to maximally tolerated doses before starting a 'fourth-line' drug such as a mineralocorticoid receptor (MR) antagonist. Although the best fourth-line drug for aTRH has not been extensively investigated, a number of studies summarized here show that an MR antagonist is effective in reducing BP when added to the standard multi-drug regimen.

  8. Evaluation of the effects of occupational noise exposure on serum aldosterone and potassium among industrial workers

    Directory of Open Access Journals (Sweden)

    Sajad Zare

    2016-01-01

    Full Text Available The existing literature indicates that occupational exposure to noise may have adverse effects on workers′ health. The aim of this study was to evaluate the possible effects of exposure to different sound pressure levels (SPLs on serum aldosterone and potassium concentration among Iranian blue collar workers in Golgohar Mining and Industrial Company in Sirjan, Kerman Province, Iran. This case-control study was performed on 45 workers of Golgohar Mining and Industrial Company. The subjects consisted of 30 workers from manufacturing departments and 15 office employees of the mining company. The controls, mainly with administrative jobs were exposed to 72 dBA SPL. Cases, in two separate groups, were exposed to noise levels of 88 dBA and 103 dBA, respectively. Noise intensity was measured at the desired locations. Noise measurements were performed according to the International Organization for Standardization (ISO 9612. To measure the serum aldosterone and potassium concentrations, a 5 mL blood sample was taken from each worker at the specified time intervals and aldosterone concentration was determined using enzyme-linked immunosorbent assay (ELISA test in the laboratory. Repeated measurement and Spearman′s correlation coefficient analysis were used with α = 0.05. Exposure to the different levels of sound pressure resulted in different aldosterone concentrations and meanwhile an increase in the SPL did not affect the concentration of potassium. From 10:00 AM to 10:30 AM, as SPL increased, aldosterone concentrations did not increase significantly but from 13:30 PM to 14:00 PM, raised SPL led to a significant increase in aldosterone concentration. However, there was no correlation between the concentration of potassium and different factors. This study indicated that increases in SPLs affect aldosterone concentration but at the same time do not have significant effects on serum potassium level.

  9. [Renin-angiotensin-aldosterone system in diabetes insipidus].

    Science.gov (United States)

    Kirillov, G; Ankov, V

    1980-01-01

    Plasma renin activity (PR) and plasma aldosterone level (PA) were investigated in 38 patients with central diabetes incipidus under conditions of standard sodium intake and after a three-day reduction of sodium in the diet with an additional furosemide load. Blood was recovered for examination in the morning under complete rest and after a two-hour slow walk. Apparently healthy volunteers (20) served as control. The PR and PA content was determined by the radioimmunological method. Not only the basic, but also the stimulated renin secretion was increased in patients with diabetes incipidus. The basic PA level was significantly diminished; after stimulation its level did not differ from that in healthy persons. At rest and with decreased sodium intake the patients displayed two types of PR activity: in some (n=18) there was no elevation, and in other (n=19) the rise was marked. It is supposed that in diabetes incipidus hyperreninemia was compensatory, directed to water retention in the organism; apparently it participated in the mechanism of hypovolemic thirst. An unusual combination of increased PR with diminished PA level is described for the first time.

  10. Prostaglandins, catecholamines, renin and aldosterone during hypertensive and normotensive pregnancy.

    Science.gov (United States)

    Pedersen, E B; Christensen, N J; Christensen, P; Johannesen, P; Kornerup, H J; Kristensen, S; Lauritsen, J G; Leyssac, P P; Rasmussen, A B; Wohlert, M

    1982-01-01

    Urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), plasma concentrations of renin (PRC), aldosterone (PAC), noradrenaline (PNA) and adrenaline (PA) were determined in the third trimester of pregnancy, 5 days and 3 months after delivery in preeclampsia and normotensive pregnant and non-pregnant control subjects. PGE2 was higher in pregnant control subjects than in non-pregnant subjects, but reduced to non-pregnant level in preeclampsia. PGF2 alpha was the same in preeclampsia and normotensive pregnancy but higher than in the non-pregnant group. PRC and PAC were increased during pregnancy, but considerably lesser in preeclampsia than during normotensive pregnancy. PNA and PA were the same in all three groups. All parameters were normal 3 months after delivery. There were no correlations between any of the hormones and blood pressure in any of the groups. PGE2 was positively correlated to PRC. The lack of renal PGE2 in preeclampsia might be responsible for the decrease in renal blood flow and sodium excretion, and the changes in PRC and PAC are supposed to be secondary to changes in PGE2. It is hypothesised that preeclampsia is a state of prostaglandin deficiency.

  11. 醛固酮通过调节ACE2-Ang(1-7)-Mas受体轴诱导内皮细胞凋亡的研究%Aldosterone induced endothelial cell apoptosis via modulation of ACE2-Ang (1-7)-Mas receptor axis

    Institute of Scientific and Technical Information of China (English)

    张霞; 潘瑜; 金惠敏

    2013-01-01

    目的 探讨醛固酮对内皮细胞ACE2-Ang(1-7)-Mas受体轴的影响及其与凋亡的关系.方法 将体外培养的人脐静脉内皮细胞(HUVEC)分为对照组(DMEM/F12培养基)、醛固酮组(10、100、1 000 nmol/L醛固酮干预)和醛固酮拮抗组(100 nmol/L醛固酮+1μmol/L醛固酮受体拮抗剂共同干预).采用免疫荧光细胞化学染色法观察细胞ACE2蛋白的表达;Western blotting检测细胞中ACE2和Mas受体的表达;酶联免疫吸附实验(ELISA)检测细胞培养上清中AngⅡ和Ang(1-7)蛋白的含量以及凋亡相关蛋白caspase-3的活性;流式细胞术结合FITC-Annexin V/PI荧光染色检测细胞凋亡.结果 与对照组比较,醛固酮组细胞ACE2和Mas受体的表达明显下调(P<0.01),并呈浓度依赖性.在100 nmol/L醛固酮组,随着干预时间的延长,细胞ACE2和Mas受体的表达明显下调(P<0.01),呈时间依赖性;而醛固酮拮抗组细胞ACE2和Mas受体的表达显著高于100 nmol/L醛固酮组(P<0.01).ELISA检测结果显示,随着干预时间的延长,醛固酮组细胞培养上清中AngⅡ浓度和caspase-3活性均显著升高,而Ang(1-7)浓度降低.流式细胞术检测结果显示:醛固酮组细胞凋亡率显著高于对照组,醛固酮拮抗组细胞凋亡率显著低于醛固酮组(P<0.05).结论 醛固酮具有调节ACE2-Ang(1-7)-Mas受体轴的作用,并可能通过此轴诱导内皮细胞凋亡.%Objective To investigate the effect of aldosterone on ACE2 - Ang ( 1 -7) - Mas receptor axis of endothelial cells, and explore its association with apoptosis. Methods Human umbilical vein endothelial cells ( HUVEC) cultured in vitro were divided into control group ( DMEM/F12 culture medium), aldosterone group (treatment with 10, 100, 1 000 nmol/L aldosterone) and aldosterone antagonist group ( 100 nmol/L aldosterone + 1 μmol/L aldosterone antagonist) . The expression of ACE2 protein in cells was observed with immunofluorescence cytochemical staining, the expression of

  12. Alterations in vascular function in primary aldosteronism: a cardiovascular magnetic resonance imaging study.

    Science.gov (United States)

    Mark, P B; Boyle, S; Zimmerli, L U; McQuarrie, E P; Delles, C; Freel, E M

    2014-02-01

    Excess aldosterone is associated with increased cardiovascular risk. Aldosterone has a permissive effect on vascular fibrosis. Cardiovascular magnetic resonance imaging (CMR) allows study of vascular function by measuring aortic distensibility. We compared aortic distensibility in primary aldosteronism (PA), essential hypertension (EH) and normal controls and explored the relationship between aortic distensibility and pulse wave velocity (PWV). We studied PA (n=14) and EH (n=33) subjects and age-matched healthy controls (n=17) with CMR, including measurement of aortic distensibility, and measured PWV using applanation tonometry. At recruitment, PA and EH patients had similar blood pressure and left ventricular mass. Subjects with PA had significantly lower aortic distensibility and higher PWV compared with EH and healthy controls. These changes were independent of other factors associated with reduced aortic distensibility, including ageing. There was a significant relationship between increasing aortic stiffness and age in keeping with physical and vascular ageing. As expected, aortic distensibility and PWV were closely correlated. These results demonstrate that PA patients display increased arterial stiffness compared with EH, independent of vascular ageing. The implication is that aldosterone invokes functional impairment of arterial function. The long-term implications of arterial stiffening in aldosterone excess require further study.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-01-01

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

  14. Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: Possible involvement of bone morphogenetic protein-6 actions

    OpenAIRE

    Otani, Hiroyuki; Otsuka, Fumio; Inagaki, Kenichi; Suzuki, Jiro; Miyoshi, Tomoko; KANO, YOSHIHIRO; GOTO, Junko; Ogura, Toshio; Makino, Hirofumi

    2008-01-01

    Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6...

  15. Reference Values for Aldosterone-Renin Ratios in Normotensive Individuals and Effect of Changes in Dietary Sodium Consumption

    NARCIS (Netherlands)

    Kerstens, Michiel N.; Kobold, Anneke C. Muller; Volmer, Marcel; Koerts, Jan; Sluiter, Wim J.; Dullaart, Robin P. F.

    2011-01-01

    BACKGROUND: Determination of the aldosterone-to-renin ratio (ARR) in blood is the preferred screening test for primary aldosteronism. Renin can be measured as the plasma renin activity (PRA) or the plasma renin concentration (PRC). Consequently, the ARR can be measured either based on the PRA (ARR(p

  16. Long-term aldosterone treatment induces decreased apical but increased basolateral expression of AQP2 in CCD of rat kidney

    NARCIS (Netherlands)

    Seigneux, S. de; Nielsen, J.; Olesen, E.T.; Dimke, H.; Kwon, T.H.; Frokiaer, J.; Nielsen, S.

    2007-01-01

    The purpose of the present studies was to determine the effects of high-dose aldosterone and dDAVP treatment on renal aquaporin-2 (AQP2) regulation and urinary concentration. Rats were treated for 6 days with either vehicle (CON; n = 8), dDAVP (0.5 ng/h, dDAVP, n = 10), aldosterone (Aldo, 150 microg

  17. Protein kinase D1 modulates aldosterone-induced ENaC activity in a renal cortical collecting duct cell line.

    LENUS (Irish Health Repository)

    McEneaney, Victoria

    2010-08-30

    Aldosterone treatment of M1-CCD cells stimulated an increase in epithelial Na(+) channel (ENaC) alpha-subunit expression that was mainly localized to the apical membrane. PKD1-suppressed cells constitutively expressed ENaCalpha at low abundance, with no increase after aldosterone treatment. In the PKD1-suppressed cells, ENaCalpha was mainly localized proximal to the basolateral surface of the epithelium both before and after aldosterone treatment. Apical membrane insertion of ENaCbeta in response to aldosterone treatment was also sensitive to PKD1 suppression as was the aldosterone-induced rise in the amiloride-sensitive, trans-epithelial current (I(TE)). The interaction of the mineralocorticoid receptor (MR) with specific elements in the promoters of aldosterone responsive genes is stabilized by ligand interaction and phosphorylation. PKD1 suppression inhibited aldosterone-induced SGK-1 expression. The nuclear localization of MR was also blocked by PKD1 suppression and MEK antagonism implicating both these kinases in MR nuclear stabilization. PKD1 thus modulates aldosterone-induced ENaC activity through the modulation of sub-cellular trafficking and the stabilization of MR nuclear localization.

  18. Tetrahydroindolizinone NK1 antagonists.

    Science.gov (United States)

    Bao, Jianming; Lu, Huagang; Morriello, Gregori J; Carlson, Emma J; Wheeldon, Alan; Chicchi, Gary G; Kurtz, Marc M; Tsao, Kwei-Lan C; Zheng, Song; Tong, Xinchun; Mills, Sander G; DeVita, Robert J

    2010-04-01

    A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles.

  19. Diagnosing and Managing Primary Aldosteronism in Hypertensive Patients: a Case-Based Approach.

    Science.gov (United States)

    Carey, Robert M

    2016-10-01

    Primary aldosteronism with a prevalence of 8 % of hypertension and 20 % of pharmacologically resistant hypertension is the most common secondary cause of hypertension. Yet, the diagnosis is missed in the vast majority of patients. Current clinical practice guidelines recommend screening for primary aldosteronism in patients with sustained elevation of blood pressure (BP) ≥150/100 mmHg if possible prior to initiation of antihypertensive therapy, and in patients with resistant hypertension, spontaneous or diuretic-induced hypokalemia, adrenal incidentaloma, obstructive sleep apnea, a family history of early onset of hypertension or cerebrovascular accident aldosteronism. Clinical and laboratory methods of screening, confirmatory testing, subtype classification, and medical and surgical management are systematically reviewed and illustrated with a clinical case.

  20. Effect of a multistage ultraendurance triathlon on aldosterone, vasopressin, extracellular water and urine electrolytes.

    Science.gov (United States)

    Knechtle, B; Morales, N P Hernández; González, E Ruvalcaba; Gutierrez, A A Aguirre; Sevilla, J Noriega; Gómez, R Amézquita; Robledo, A R Estrada; Rodríguez, A L Marroquín; Fraire, O Salas; Andonie, J L; Lopez, L C; Kohler, G; Rosemann, T

    2012-02-01

    Prolonged endurance exercise over several days induces increase in extracellular water (ECW). We aimed to investigate an association between the increase in ECW and the change in aldosterone and vasopressin in a multistage ultraendurance triathlon, the 'World Challenge Deca Iron Triathlon' with 10 Ironman triathlons within 10 days. Before and after each Ironman, body mass, ECW, urinary [Na(+)], urinary [K(+)], urinary specific gravity, urinary osmolality and aldosterone and vasopressin in plasma were measured. The 11 finishers completed the total distance of 38 km swimming, 1800 km cycling and 422 km running within 145.5 (18.8) hours and 25 (22) minutes. ECW increased by 0.9 (1.1) L from 14.6 (1.5) L prerace to 15.5 (1.9) L postrace (P triathlon, but vasopressin did not. The increase in ECW and the increase in aldosterone were not associated.

  1. Regulation of aldosterone in the guinea-pig--effect of oestrus cycle, pregnancy and sodium status.

    Science.gov (United States)

    Whipp, G T; Wintour, E M; Coghlan, J P; Scoggins, B A

    1976-02-01

    The blood concentrations of aldosterone, corticosterone and cortisol were measured in conscious, non-stressed guinea-pigs using a double isotope dilution derivative assay procedure. Aldosterone levels in the guinea-pig were high when compared with those of other species. The concentration of aldosterone, 37-7 +/- 15-9 ng/100 ml (x +/- SD), and cortisol, 31-8 +/- 10-1 mug/100 ml, found in non-pregnant females on a moderate sodium intake was significantly greater than in males (aldosterone 22-2 +/- 2-4 ng/100 ml and cortisol 19-3 +/- 5-7 mug/100 ml). There was no sex difference in corticosterone concentrations; females, 0-25 +/- 0-06 mug/100 ml and males, 0-23 +/- 0-10 mug/100 ml. The oestrus cycle had no effect on levels of the three steroids measured. Two thirds of the way through the 68-day gestation period aldosterone levels were significantly elevated compared with non-pregnant values (68-7 +/- 50-9 ng/100 ml, p less than 0-05). Values at day 20 (33-2 +/- 11-7 ng/100 ml) and day 60 of gestation (51-9 +/- 21-7 ng/100 ml) were similar to those of non-pregnant animals. Cortisol and corticosterone levels were significantly elevated at 20 days gestation and they continued to rise until, at day 60, cortisol was 9 times and corticosterone 4 times higher than the non-pregnant values. Compared with a moderate Na intake, salt loading suppressed aldosterone levels and Na restriction raised them.

  2. Long-term treatment with aldosterone slows the progression of age-related hearing loss.

    Science.gov (United States)

    Halonen, Joshua; Hinton, Ashley S; Frisina, Robert D; Ding, Bo; Zhu, Xiaoxia; Walton, Joseph P

    2016-06-01

    Age-related hearing loss (ARHL), clinically referred to as presbycusis, is one of the three most prevalent chronic medical conditions of our elderly, with the majority of persons over the age of 60 suffering from some degree of ARHL. The progressive loss of auditory sensitivity and perceptual capability results in significant declines in workplace productivity, quality of life, cognition and abilities to communicate effectively. Aldosterone is a mineralocorticoid hormone produced in the adrenal glands and plays a role in the maintenance of key ion pumps, including the Na-K(+)-Cl co-transporter 1 or NKCC1, which is involved in homeostatic maintenance of the endocochlear potential. Previously we reported that aldosterone (1 μM) increases NKCC1 protein expression in vitro and that this up-regulation of NKCC1 was not dose-dependent (dosing range from 1 nM to 100 μM). In the current study we measured behavioral and electrophysiological hearing function in middle-aged mice following long-term systemic treatment with aldosterone. We also confirmed that blood pressure remained stable during treatment and that NKCC1 protein expression was upregulated. Pre-pulse inhibition of the acoustic startle response was used as a functional measure of hearing, and the auditory brainstem response was used as an objective measure of peripheral sensitivity. Long-term treatment with aldosterone improved both behavioral and physiological measures of hearing (ABR thresholds). These results are the first to demonstrate a protective effect of aldosterone on age-related hearing loss and pave the way for translational drug development, using aldosterone as a key component to prevent or slow down the progression of ARHL.

  3. Aldosterone and cortisol co-secreting bifunctional adrenal cortical carcinoma: A rare event.

    Science.gov (United States)

    Chowdhury, Puskar Shyam; Nayak, Prasant; Gurumurthy, Srinivasan; David, Deepak

    2014-07-01

    Adrenocortical carcinoma (ACC) co-secreting aldosterone and cortisol is extremely rare. We report the case of a 37-yearold female who presented with paresis and facial puffiness. Evaluation revealed hypertension, hyperglycemia, severe hypokalemia and hyperaldosteronemia with elevated plasma aldosterone to renin ratio (ARR). Urinary free cortisol estimation showed elevated levels. Computed tomography scan revealed a right adrenal mass. Radical adrenalectomy specimen revealed ACC (T3N1). Post-operatively, the patient became normotensive and euglycemic with normalization of urinary cortisol and ARR. This case highlights the need for a complete evaluation in patients of hyperaldosteronism if overlapping symptoms of hypercortisolism are encountered, to avoid post-operative adrenal crisis.

  4. Aldosterone and angiotensin II induced protein aggregation in renal proximal tubules

    DEFF Research Database (Denmark)

    Cheema, Muhammad Umar; Poulsen, Ebbe Toftgaard; Enghild, Jan J;

    2013-01-01

    systems in the kidney from control rats and rats receiving aldosterone or angiotensin II treatment for 7 days. Control rats formed both aggresomes and autophagosomes specifically in the proximal tubules, indicating a need for these structures even under baseline conditions. Fluorescence sorted aggresomes...... contained various rat keratins known to be expressed in renal tubules as assessed by protein mass spectrometry. Aldosterone administration increased the abundance of the proximal tubular aggresomal protein keratin 5, the ribosomal protein RPL27, ataxin-3, and the chaperone heat shock protein 70...

  5. Aldosterone-mineralocorticoid receptor promotes urine prostasin through glomerular barrier injury and not tissue abundance

    DEFF Research Database (Denmark)

    Stolzenburg Oxlund, Christina; Kurt, B.; Schwarzensteiner, I.

    2015-01-01

    Objective: Low salt intake or infusion with the mineralocorticoid hormone aldosterone increases the abundance of proteolytically activated gamma ENaC in rat kidney. Prostasin is a serine proteinase GPI-anchored to the apical membrane of renal principal cells. It was hypothesized that the aldoster......Objective: Low salt intake or infusion with the mineralocorticoid hormone aldosterone increases the abundance of proteolytically activated gamma ENaC in rat kidney. Prostasin is a serine proteinase GPI-anchored to the apical membrane of renal principal cells. It was hypothesized...

  6. PF-03882845, a non-steroidal mineralocorticoid receptor antagonist, prevents renal injury with reduced risk of hyperkalemia in an animal model of nephropathy

    Directory of Open Access Journals (Sweden)

    Stephen eOrena

    2013-10-01

    Full Text Available The mineralocorticoid receptor (MR antagonists PF 03882845 and eplerenone were evaluated for renal protection against aldosterone mediated renal disease in uninephrectomized Sprague Dawley (SD rats maintained on a high salt diet and receiving aldosterone by osmotic mini pump for 27 days. Serum K+ and the urinary albumin to creatinine ratio (UACR were assessed following 14 and 27 days of treatment. Aldosterone induced renal fibrosis as evidenced by increases in UACR, collagen IV staining in kidney cortex, and expression of pro fibrotic genes relative to sham operated controls not receiving aldosterone. While both PF 03882845 and eplerenone elevated serum K+ levels with similar potencies, PF 03882845 was more potent than eplerenone in suppressing the rise in UACR. PF 03882845 prevented the increase in collagen IV staining at 5, 15 and 50 mg/kg BID while eplerenone was effective only at the highest dose tested (450 mg/kg BID. All doses of PF 03882845 suppressed aldosterone induced increases in collagen IV, transforming growth factor 1 (Tgf 1, interleukin 6 (Il-6, intermolecular adhesion molecule 1 (Icam-1 and osteopontin gene expression in kidney while eplerenone was only effective at the highest dose. The therapeutic index (TI, calculated as the ratio of the EC50 for increasing serum K+ to the EC50 for UACR lowering, was 83.8 for PF 03882845 and 1.47 for eplerenone. Thus the TI of PF 03882845 against hyperkalemia was 57 fold superior to that of eplerenone indicating that PF 03882845 may present significantly less risk for hyperkalemia compared to eplerenone.

  7. Development of Sensitive and Direct Methods for Measuring Plasma Aldosterone and Catecholamine Concentrations

    Science.gov (United States)

    Haber, E.

    1972-01-01

    Radioimmunoassays for renin activity, angiotensin 1, and angiotensin 2 in the study of vasomotor regulation give new insight into the role of the renin system in maintaining postural homeostatsis. Similar laboratory procedures for specific assays of aldosterone and catecholamines achieve accurate determinations in small human blood samples.

  8. Effect of Salvia Miltiorrhiza on Left Ventricular Hypertrophy and Cardiac Aldosterone in Spontaneously Hypertensive Rats

    Institute of Scientific and Technical Information of China (English)

    韩少杰; 郑智; 任大宏

    2002-01-01

    Summary: Chronic treatment with Salvia Miltiorrhiza preventing left ventricular hypertrophy(LVH) and its possible mechanism-inhibiting the action of cardiac aldosterone in spontaneouslyhypertensive rats (SHR) were investigated. Normotensive Wistar-kyoto (WKY) rats and SHRswere used. Part of SHRs was treated with Salvia Miltiorrhiza for 12 weeks. Systolic blood pres-sure (SBP) and left ventricular mass index were measured. Sections of heart tissue were stainedwith HE method and VanGieson method. Collagen volume fraction was determined in the left ven-tricle by automatically quantitative morphometry. Cardiac aldosterone concentration was measuredby radioimmunoassay. The results indicated that compared with WKY rats, SHRs exhibited high-er SBP, left ventricular collagen volume fraction, and aldosterone concentration (all P<0. 05).After the treatment with Salvia Miltiorrhiza, SBP, left ventricular collagen volume fraction, andaldosterone concentration in SHR were decreased as compared with control group (P<0. 05) ex-cept SBP. It was concluded that chronic treatment with Salvia Miltiorrhiza could prevent left ven-tricular hypertrophy in SHR, significantly inhibit collagen compositions in left ventricle. Themechanism was probably related with the inhibition of the cardiac aldosterone action.

  9. Plasma aldosterone concentrations and plasma renin activity in healthy dogs and dogs with hyperadrenocorticism

    NARCIS (Netherlands)

    Javadi, S; Mol, JA; Boer, P; Boer, WH; Runberk, A

    2003-01-01

    The mean (se) basal plasma aldosterone concentrations were significantly lower in 31 dogs with pituitary-dependent hyperadrenocorticism (PDH) (75 [9] pmol/litre) than in 12 healthy dogs (118 [14] pmol/litre), whereas in five dogs with hyperadrenocorticism due to an adrenocortical tumour they were si

  10. Application and evaluation of postural stimulation test and captopril challenge test in diagnosis of primary aldosteronism

    Institute of Scientific and Technical Information of China (English)

    郝岩

    2014-01-01

    Methods One hundred and twenty-eight patients with essential hypertension and 71 patients with primary aldosteronism were included in this study.The efficacy of different diagnostic indices of postural stimulation test(PST)with captopril challenge test(CCT)were compared by constructing receiver operating characteristic curve.The

  11. Modulation of Immunity and Inflammation by the Mineralocorticoid Receptor and Aldosterone

    Directory of Open Access Journals (Sweden)

    N. Muñoz-Durango

    2015-01-01

    Full Text Available The mineralocorticoid receptor (MR is a ligand dependent transcription factor. MR has been traditionally associated with the control of water and electrolyte homeostasis in order to keep blood pressure through aldosterone activation. However, there is growing evidence indicating that MR expression is not restricted to vascular and renal tissues, as it can be also expressed by cells of the immune system, where it responds to stimulation or antagonism, controlling immune cell function. On the other hand, aldosterone also has been associated with proinflammatory immune effects, such as the release of proinflammatory cytokines, generating oxidative stress and inducing fibrosis. The inflammatory participation of MR and aldosterone in the cardiovascular disease suggests an association with alterations in the immune system. Hypertensive patients show higher levels of proinflammatory mediators that can be modulated by MR antagonism. Although these proinflammatory properties have been observed in other autoimmune and chronic inflammatory diseases, the cellular and molecular mechanisms that mediate these effects remain unknown. Here we review and discuss the scientific work aimed at determining the immunological role of MR and aldosterone in humans, as well as animal models.

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

    NARCIS (Netherlands)

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

    2006-01-01

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

  13. Genomic and nongenomic effects of aldosterone in the rat heart : why is spironolactone cardioprotective?

    NARCIS (Netherlands)

    Chai, WX; Garrelds, IM; Arulmani, U; Schoemaker, RG; Lamers, JMJ; Danser, AHJ

    2005-01-01

    1 Mineralocorticoid receptor (MR) antagonism with spironolactone reduces mortality in heart failure on top of ACE inhibition. To investigate the underlying mechanism, we compared the actions of both aldosterone and spironolactone to those of angiotensin (Ang) II in the rat heart. 2 Hearts of male Wi

  14. Congenital hyperreninemic hypoaldosteronism unlinked to the aldosterone synthase (CYP11B2) gene.

    Science.gov (United States)

    Kayes-Wandover, K M; Tannin, G M; Shulman, D; Peled, D; Jones, K L; Karaviti, L; White, P C

    2001-11-01

    Isolated hyperreninemic hypoaldosteronism presenting in infancy is usually caused by mutations in the CYP11B2 gene encoding aldosterone synthase. We studied five patients in four unrelated kindreds with hyperreninemic hypoaldosteronism, in whom we were unable to find such mutations. All presented in infancy with failure to thrive, hyponatremia, hyperkalemia, markedly elevated plasma renin activity, and low or inappropriately normal aldosterone levels. All had normal cortisol levels and no signs or symptoms of congenital adrenal hyperplasia. All responded to fludrocortisone treatment. There were no mutations detected in exons or splice junctions of CYP11B2. Linkage of the disorder to CYP11B2 was studied in two unrelated consanguineous patients and in an affected sib pair. The consanguineous patients were each heterozygous for at least one of three polymorphic microsatellite markers near CYP11B2, excluding linkage to CYP11B2. However, linkage of the disease to CYP11B2 could not be excluded in the affected sib pair. Genes involved in the regulation of aldosterone biosynthesis, including those encoding angiotensinogen, angiotensin-converting enzyme, and the AT1 angiotensin II receptor were similarly excluded from linkage. These results demonstrate the existence of an inherited form of hyperreninemic hypoaldosteronism distinct from aldosterone synthase deficiency. The affected gene(s) remain to be determined.

  15. Progress of Aldosterone Breakthroughs%醛固酮逃逸的研究进展

    Institute of Scientific and Technical Information of China (English)

    郭建淑

    2011-01-01

    Renin-angiotensin-aldosterone system inhibitors have become leading drugs in the treatment of hypertension and chronic heart failure. Angiotensin-converting-enzyme inhibitors( ACEI) and angiotensin-receptor blockers ( ARB) do not, however, uniformly suppress the renin-angiotensin-aldosterone system. After a period of therapy with ACEI or ARB, plasma aldosterone levels are elevated in some patients. This phenomenon, is known as 'aldosterone escape' or 'aldosterone breakthrough'. The key questions of how breakthrough happens , how often breakthrough occurs and whether breakthrough leads, to worse outcomes have yet to be definitively answered. This review summarizes reported research on the incidence and mechanism of aldosterone breakthrough, we also discuss the difference of aldosterone breakthrough during the treatment with ACEI or ARB.%肾素-血管紧张素-醛固酮系统抑制剂已成为治疗高血压及心力衰竭的主要药物,然而血管紧张素转换酶抑制剂与血管紧张素Ⅱ受体拮抗剂并没有充分的阻断过度激活的肾素-血管紧张素-醛固酮系统.在经过血管紧张素转换酶抑制剂或血管紧张素Ⅱ受体拮抗剂治疗一段时间后,一部分患者血浆醛固酮水平有所升高,即"醛固酮逃逸现象".该现象的发生率及机制,对临床治疗的影响等重要问题一直不完全清楚,现就醛固醛逃逸现象的发生率、机制、在血管紧张素转换酶抑制剂和血管紧张素Ⅱ受体拮抗剂治疗中的区别等在近年的研究进展做一概要的综述.

  16. Central endogenous angiotensin-(1-7) protects against aldosterone/NaCl-induced hypertension in female rats.

    Science.gov (United States)

    Xue, Baojian; Zhang, Zhongming; Johnson, Ralph F; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2013-09-01

    In comparison to male rodents, females are protected against angiotensin (ANG) II- and aldosterone (Aldo)-induced hypertension. However, the mechanisms underlying this protective effect are not well understood. ANG-(1-7) is formed from ANG II by angiotensin-converting enzyme 2 (ACE2) and has an antihypertensive effect in the central nervous system (CNS). The present study tested the hypothesis that central ANG-(1-7) plays an important protective role in attenuating the development of Aldo/NaCl-hypertension in female rats. Systemic infusion of Aldo into intact female rats with 1% NaCl as their sole drinking fluid resulted in a slight increase in blood pressure (BP). Intracerebroventricular (icv) infusion of A-779, an ANG-(1-7) receptor (Mas-R) antagonist, significantly augmented the pressor effects of Aldo/NaCl. In contrast, systemic Aldo/NaCl induced a significant increase in BP in ovariectomized (OVX) female rats, and central infusion of ANG-(1-7) significantly attenuated this Aldo/NaCl pressor effect. The inhibitory effect of ANG-(1-7) on the Aldo/NaCl pressor effect was abolished by concurrent infusion of A-779. RT-PCR analyses showed that there was a corresponding change in mRNA expression of several renin-angiotensin system components, estrogen receptors and an NADPH oxidase subunit in the lamina terminalis. Taken together these results suggest that female sex hormones regulate an antihypertensive axis of the brain renin-angiotensin system involving ACE2/ANG-(1-7)/Mas-R that plays an important counterregulatory role in protecting against the development of Aldo/NaCl-induced hypertension.

  17. Rationale and Design of the ATHENA-HF Trial: Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure.

    Science.gov (United States)

    Butler, Javed; Hernandez, Adrian F; Anstrom, Kevin J; Kalogeropoulos, Andreas; Redfield, Margaret M; Konstam, Marvin A; Tang, W H Wilson; Felker, G Michael; Shah, Monica R; Braunwald, Eugene

    2016-09-01

    Although therapy with mineralocorticoid receptor antagonists (MRAs) is recommended for patients with chronic heart failure (HF) with reduced ejection fraction and in post-infarction HF, it has not been studied well in acute HF (AHF) despite being commonly used in this setting. At high doses, MRA therapy in AHF may relieve congestion through its natriuretic properties and mitigate the effects of adverse neurohormonal activation associated with intravenous loop diuretics. The ATHENA-HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) trial is a randomized, double-blind, placebo-controlled study of the safety and efficacy of 100 mg/day spironolactone versus placebo (or continued low-dose spironolactone use in participants who are already receiving spironolactone at baseline) in 360 patients hospitalized for AHF. Patients are randomized within 24 h of receiving the first dose of intravenous diuretics. The primary objective is to determine if high-dose spironolactone, compared with standard care, will lead to greater reductions in N-terminal pro-B-type natriuretic peptide levels from randomization to 96 h. The secondary endpoints include changes in the clinical congestion score, dyspnea relief, urine output, weight change, loop diuretic dose, and in-hospital worsening HF. Index hospital length of stay and 30-day clinical outcomes will be assessed. Safety endpoints include risk of hyperkalemia and renal function. Differences among patients with reduced versus preserved ejection fraction will be determined. (Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure [ATHENA-HF]; NCT02235077).

  18. Subchronic treatment with aldosterone induces depression-like behaviours and gene expression changes relevant to major depressive disorder.

    Science.gov (United States)

    Hlavacova, Natasa; Wes, Paul D; Ondrejcakova, Maria; Flynn, Marianne E; Poundstone, Patricia K; Babic, Stanislav; Murck, Harald; Jezova, Daniela

    2012-03-01

    The potential role of aldosterone in the pathophysiology of depression is unclear. The aim of this study was to test the hypothesis that prolonged elevation of circulating aldosterone induces depression-like behaviour accompanied by disease-relevant changes in gene expression in the hippocampus. Subchronic (2-wk) treatment with aldosterone (2 μg/100 g body weight per day) or vehicle via subcutaneous osmotic minipumps was used to induce hyperaldosteronism in male rats. All rats (n = 20/treatment group) underwent a modified sucrose preference test. Half of the animals from each treatment group were exposed to the forced swim test (FST), which served both as a tool to assess depression-like behaviour and as a stress stimulus. Affymetrix microarray analysis was used to screen the entire rat genome for gene expression changes in the hippocampus. Aldosterone treatment induced an anhedonic state manifested by decreased sucrose preference. In the FST, depressogenic action of aldosterone was manifested by decreased latency to immobility and increased time spent immobile. Aldosterone treatment resulted in transcriptional changes of genes in the hippocampus involved in inflammation, glutamatergic activity, and synaptic and neuritic remodelling. Furthermore, aldosterone-regulated genes substantially overlapped with genes affected by stress in the FST. This study demonstrates the existence of a causal relationship between the hyperaldosteronism and depressive behaviour. In addition, aldosterone treatment induced changes in gene expression that may be relevant to the aetiology of major depressive disorder. Subchronic treatment with aldosterone represents a new animal model of depression, which may contribute to the development of novel targets for the treatment of depression.

  19. Optimization of left adrenal vein sampling in primary aldosteronism: Coping with asymmetrical cortisol secretion.

    Science.gov (United States)

    Kishino, Mitsuhiro; Yoshimoto, Takanobu; Nakadate, Masashi; Katada, Yoshiaki; Kanda, Eiichiro; Nakaminato, Shuichiro; Saida, Yukihisa; Ogawa, Yoshihiro; Tateishi, Ukihide

    2017-03-31

    We evaluated the influence of catheter sampling position and size on left adrenal venous sampling (AVS) in patients with primary aldosteronism (PA) and analyzed their relationship to cortisol secretion. This retrospective study included 111 patients with a diagnosis of primary aldosteronism who underwent tetracosactide-stimulated AVS. Left AVS was obtained from two catheter positions - the central adrenal vein (CAV) and the common trunk. For common trunk sampling, 5-French catheters were used in 51 patients, and microcatheters were used in 60 patients. Autonomous cortisol secretion was evaluated with a low-dose dexamethasone suppression test in 87 patients. The adrenal/inferior vena cava cortisol concentration ratio [selectivity index (SI)] was significantly lower in samples from the left common trunk than those of the left CAV and right adrenal veins, but this difference was reduced when a microcatheter was used for common trunk sampling. Sample dilution in the common trunk of the left adrenal vein can be decreased by limiting sampling speed with the use of a microcatheter. Meanwhile, there was no significant difference in SI between the left CAV and right adrenal veins. Laterality, determined according to aldosterone/cortisol ratio (A/C ratio) based criteria, showed good reproducibility regardless of sampling position, unlike the absolute aldosterone value based criteria. However, in 11 cases with autonomous cortisol co-secretion, the cortisol hypersecreting side tended to be underestimated when using A/C ratio based criteria. Left CAV sampling enables symmetrical sampling, and may be essential when using absolute aldosterone value based criteria in cases where symmetrical cortisol secretion is uncertain.

  20. Leptin Induces Hypertension and Endothelial Dysfunction via Aldosterone-Dependent Mechanisms in Obese Female Mice.

    Science.gov (United States)

    Huby, Anne-Cécile; Otvos, Laszlo; Belin de Chantemèle, Eric J

    2016-05-01

    Obesity is a major risk factor for cardiovascular disease in males and females. Whether obesity triggers cardiovascular disease via similar mechanisms in both the sexes is, however, unknown. In males, the adipokine leptin highly contributes to obesity-related cardiovascular disease by increasing sympathetic activity. Females secrete 3× to 4× more leptin than males, but do not exhibit high sympathetic tone with obesity. Nevertheless, females show inappropriately high aldosterone levels that positively correlate with adiposity and blood pressure (BP). We hypothesized that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in females. Leptin control of the cardiovascular function was analyzed in female mice sensitized to leptin via the deletion of protein tyrosine phosphatase 1b (knockout) and in agouti yellow obese hyperleptinemic mice (Ay). Hypersensitivity to leptin (wild-type, 115 ± 2; protein tyrosine phosphatase 1b knockout, 124 ± 2 mm Hg; Pleptin receptor antagonism restored BP and endothelial function in protein tyrosine phosphatase 1b knockout and Ay mice. Hypersensitivity to leptin and obesity reduced BP response to ganglionic blockade in both strains and plasma catecholamine levels in protein tyrosine phosphatase 1b knockout mice. Hypersensitivity to leptin and obesity significantly increased plasma aldosterone levels and adrenal CYP11B2 expression. Chronic leptin receptor antagonism reduced aldosterone levels. Furthermore, chronic leptin and mineralocorticoid receptor blockade reduced BP and improved endothelial function in both leptin-sensitized and obese hyperleptinemic female mice. Together, these data demonstrate that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in female mice and suggest that obesity leads to cardiovascular disease via sex-specific mechanisms.

  1. Inverse relation between aldosterone and venous capacitance in chronically treated congestive heart failure.

    Science.gov (United States)

    Rietzschel, E; Duprez, D A; De Buyzere, M L; Clement, D L

    2000-04-15

    The purpose of this study was to examine if there is a relation between the aldosterone escape phenomenon and venous capacitance of the upper and lower limbs in patients with long-term congestive heart failure (CHF) receiving chronic treatment with angiotensin-converting enzyme (ACE) inhibitors. The study group consisted of 16 subjects with ischemic CHF in New York Heart Association functional class II (age 59 +/-2 years, ejection fraction 24+/-4%), stabilized under a constant drug regimen comprising furosemide, captopril 50 mg 3 times daily, and digoxin for at least 3 months. Thirteen apparently healthy volunteers, aged 50+/-4 years acted as controls. Forearm and calf venous capacitances were measured simultaneously by venous occlusion plethysmography using mercury-in-silastic strain gauges. The equilibration technique was used to derive venous capacitance from the recorded pressure-volume curves. Active renin, angiotensin II, and aldosterone levels were determined on venous blood samples obtained in the supine position. Angiotensin II (paldosterone (paldosterone escape phenomenon). In CHF, forearm venous capacitance was 2.19+/-0.18 ml/100 ml; calf venous capacitance was 2.83+/-0.27 ml/100 ml. Aldosterone significantly and inversely correlated with venous capacitance in both upper (r = -0.586; p = 0.017) and lower (r = -0.625; p = 0.01) limbs. No correlations were found between forearm or calf venous capacitance and renin or angiotensin II. In patients with heart failure chronically treated with diuretics and full ACE inhibition, venous capacitance is inversely correlated with aldosterone through the mechanism of aldosterone escape, creating the potential for further deterioration of the CHF process.

  2. Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure.

    Science.gov (United States)

    Sica, Domenic A

    2015-01-01

    Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered.

  3. Moderate antiproteinuric effect of add-on aldosterone blockade with eplerenone in non-diabetic chronic kidney disease. A randomized cross-over study.

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    Lene Boesby

    Full Text Available BACKGROUND: Reduction of proteinuria and blood pressure (BP with blockers of the renin-angiotensin system (RAS impairs the progression of chronic kidney disease (CKD. The aldosterone antagonist spironolactone has an antiproteinuric effect, but its use is limited by side effects. The present study evaluated the short-term antiproteinuric effect and safety of the selective aldosterone antagonist eplerenone in non-diabetic CKD. STUDY DESIGN: Open randomized cross-over trial. SETTING AND PARTICIPANTS: Forty patients with non-diabetic CKD and urinary albumin excretion greater than 300 mg/24 hours. INTERVENTION: Eight weeks of once-daily administration of add-on 25-50 mg eplerenone to stable standard antihypertensive treatment including RAS-blockade. OUTCOMES & MEASUREMENTS: 24 hour urinary albumin excretion, BP, p-potassium, and creatinine clearance. RESULTS: The mean urinary albumin excretion was 22% [CI: 14,28], P < 0.001, lower during treatment with eplerenone. Mean systolic BP was 4 mmHg [CI: 2,6], P = 0.002, diastolic BP was 2 mmHg [CI: 0,4], P = 0.02, creatinine clearance was 5% [CI: 2,8], P = 0.005, lower during eplerenone treatment. After correction for BP and creatinine clearance differences between the study periods, the mean urinary albumin excretion was 14% [CI: 4,24], P = 0.008 lower during treatment. Mean p-potassium was 0.1 mEq/L [CI: 0.1,0.2] higher during eplerenone treatment, P<0.001. Eplerenone was thus well tolerated and no patients were withdrawn due to hyperkalaemia. LIMITATIONS: Open label, no wash-out period and a moderate sample size. CONCLUSIONS: In non-diabetic CKD patients, the addition of eplerenone to standard antihypertensive treatment including RAS-blockade caused a moderate BP independent fall in albuminuria, a minor fall in creatinine clearance and a 0.1 mEq/L increase in p-potassium. TRIAL REGISTRATION: Clinicaltrials.gov NCT00430924.

  4. Relationship between aldosterone and the metabolic syndrome in patients with obstructive sleep apnea hypopnea syndrome: effect of continuous positive airway pressure treatment.

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    Antonia Barceló

    Full Text Available BACKGROUND: Metabolic syndrome (MS occurs frequently in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS. We hypothesized that aldosterone levels are elevated in OSAHS and associated with the presence of MS. METHODS: We studied 66 patients with OSAHS (33 with MS and 33 without MS and 35 controls. The occurrence of the MS was analyzed according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III clinical criteria. Measurements of plasma renin activity (PRA, aldosterone, aldosterone:PRA ratio, creatinine, glucose, triglycerides, cholesterol and HDL cholesterol were obtained at baseline and after CPAP treatment. RESULTS: Aldosterone levels were associated with the severity of OSAHS and higher than controls (p = 0.046. Significant differences in aldosterone levels were detected between OSAHS patients with and without MS (p = 0.041. A significant reduction was observed in the aldosterone levels in patients under CPAP treatment (p = 0.012. CONCLUSION: This study shows that aldosterone levels are elevated in OSAHS in comparison to controls, and that CPAP therapy reduces aldosterone levels. It also shows that aldosterone levels are associated with the presence of metabolic syndrome, suggesting that aldosterone excess might predispose or aggravate the metabolic and cardiovascular complications of OSAHS. TRIAL REGISTRATION: The study is not a randomized controlled trial and was not registered.

  5. Determinants and Changes Associated with Aldosterone Breakthrough after Angiotensin II Receptor Blockade in Patients with Type 2 Diabetes with Overt Nephropathy

    Science.gov (United States)

    Moranne, Olivier; Bakris, George; Fafin, Coraline; Favre, Guillaume; Pradier, Christian

    2013-01-01

    Summary Background and objectives Inhibition of the renin-angiotensin-aldosterone system decreases proteinuria and slows estimated GFR decline in patients with type 2 diabetes mellitus with overt nephropathy. Serum aldosterone levels may increase during renin-angiotensin-aldosterone system blockade. The determinants and consequences of this aldosterone breakthrough remain unknown. Design, setting, participants, & measurements This study examined the incidence, determinants, and changes associated with aldosterone breakthrough in a posthoc analysis of a randomized study that compared the effect of two angiotensin II receptor blockers in patients with type 2 diabetes mellitus with overt nephropathy. Results Of 567 of 860 participants included in this posthoc analysis, 28% of participants developed aldosterone breakthrough, which was defined by an increase greater than 10% over baseline values of serum aldosterone levels after 1 year of angiotensin II receptor blocker treatment. Factors independently associated with aldosterone breakthrough at 1 year were lower serum aldosterone and potassium levels at baseline, higher decreases in sodium intake, systolic BP, and estimated GFR from baseline to 1 year, and use of losartan versus telmisartan. Aldosterone breakthrough at 6 months was not sustained at 1 year in 69% of cases, and it did not predict estimated GFR decrease and proteinuria increase between 6 months and 1 year. Conclusions Aldosterone breakthrough is a frequent event 1 year after initiating renin-angiotensin-aldosterone system blockade, particularly in participants exposed to intensive lowering of BP with sodium depletion and short-acting angiotensin II receptor blockers. Short-term serum aldosterone level increases at 6 months are not associated with negative kidney outcomes between 6 months and 1 year. PMID:23929924

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

    NARCIS (Netherlands)

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

    2015-01-01

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

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  8. Misdiagnosis of two cases of primary aldosteronism owing to failure of computed tomography to detect adrenal microadenoma.

    Science.gov (United States)

    Fujiwara, Mako; Murao, Koji; Imachi, Hitomi; Yoshida, Kazuya; Muraoka, Tomie; Ohyama, Tomoyo; Kushida, Yoshio; Haba, Reiji; Kakehi, Yoshiyuki; Ishida, Toshihiko

    2010-10-01

    Recent studies have suggested that primary aldosteronism (PA) is a common form of hypertension. However, some cases of PA are overlooked because microadenoma is difficult to detect by imaging. The author report 2 cases in which aldosterone-producing microadenoma was diagnosed by selective adrenal venous sampling (AVS) and furosemide plus upright test. These adenomas were resected by laparoscopic adrenalectomy. Both cases presented with hypertension and hypokalemia. Experimental data, including those obtained from furosemide plus upright test, suggested PA. In both cases, computed tomography imaging revealed a normal adrenal gland without any tumor. However, selective AVS indicated unilateral hypersecretion of aldosterone. Laparoscopic adrenalectomy was performed, and clinical symptoms of the patients improved. The histopathologic findings revealed aldosterone-producing microadenomas with diameters of 6 and 3 mm, respectively, in cases 1 and 2. In conclusion, AVS should be performed to confirm the diagnosis of PA when computed tomography imaging does not provide definite results.

  9. Aldosterone inhibits the fetal program and increases hypertrophy in the heart of hypertensive mice.

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    Feriel Azibani

    Full Text Available BACKGROUND: Arterial hypertension (AH induces cardiac hypertrophy and reactivation of "fetal" gene expression. In rodent heart, alpha-Myosin Heavy Chain (MyHC and its micro-RNA miR-208a regulate the expression of beta-MyHC and of its intronic miR-208b. However, the role of aldosterone in these processes remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: RT-PCR and western-blot were used to investigate the genes modulated by arterial hypertension and cardiac hyperaldosteronism. We developed a model of double-transgenic mice (AS-Ren with cardiac hyperaldosteronism (AS mice and systemic hypertension (Ren. AS-Ren mice had increased (x2 angiotensin II in plasma and increased (x2 aldosterone in heart. Ren and AS-Ren mice had a robust and similar hypertension (+70% versus their controls. Anatomical data and echocardiography showed a worsening of cardiac hypertrophy (+41% in AS-Ren mice (P<0.05 vs Ren. The increase of ANP (x 2.5; P<0.01 mRNA observed in Ren mice was blunted in AS-Ren mice. This non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice, as indicated by the markedly reduced cardiac hypertrophy in ANP-infused AS-Ren mice for one month. Besides, the AH-induced increase of ßMyHC and its intronic miRNA-208b was prevented in AS-Ren. The inhibition of miR 208a (-75%, p<0.001 in AS-Ren mice compared to AS was associated with increased Sox 6 mRNA (x 1.34; p<0.05, an inhibitor of ßMyHC transcription. Eplerenone prevented all aldosterone-dependent effects. CONCLUSIONS/SIGNIFICANCE: Our results indicate that increased aldosterone in heart inhibits the induction of atrial natriuretic peptide expression, via the mineralocorticoid receptor. This worsens cardiac hypertrophy without changing blood pressure. Moreover, this work reveals an original aldosterone-dependent inhibition of miR-208a in hypertension, resulting in the inhibition of β-myosin heavy chain expression through the induction

  10. Regulation of NHE3, NKCC2, and NCC abundance in kidney during aldosterone escape phenomenon: role of NO.

    Science.gov (United States)

    Turban, Sharon; Wang, Xiao-Yan; Knepper, Mark A

    2003-11-01

    Escape from aldosterone-induced renal NaCl retention is an important homeostatic mechanism in pathophysiological states in which plasma aldosterone levels are inappropriately elevated, e.g., in primary aldosteronism. Our previous studies demonstrated that the escape process occurs largely as a result of a marked suppression of the abundance of the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule but have also demonstrated a paradoxical increase in the protein abundance of the apical Na/H exchanger of the proximal tubule (NHE3). In the present study, we confirmed the increase in NHE3 and also showed that a similar increase in NHE3 protein abundance occurs in escape from ANG II-mediated NaCl retention. To investigate the potential role of nitric oxide (NO) in the observed upregulation of NHE3, we repeated the aldosterone escape experiment with a superimposed infusion of a NO synthase inhibitor, NG-nitro-l-arginine methyl ester (l-NAME). l-NAME infusion abolished the increase in NHE3 protein abundance. Furthermore, in a different experiment, NO synthase inhibition uncovered an associated decrease in the abundance of the Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb, not seen with simple aldosterone escape. However, NO synthase inhibition did not block the decrease in NCC abundance normally seen with aldosterone escape. Furthermore, l-NAME infusion in aldosterone-treated rats markedly decreased both NHE3 and NKCC2 protein abundance, without changes in the corresponding mRNA levels. We conclude that NHE3 and NKCC2 protein abundances in kidney are positively regulated by NO and that the increase in NHE3 abundance seen in the aldosterone escape phenomenon is NO dependent.

  11. High-sodium intake aggravates myocardial injuriesinduced by aldosterone via oxidative stress inSprague-Dawley rats

    Institute of Scientific and Technical Information of China (English)

    Jing-yi LI; Shao-ling ZHANG; Meng REN; Yan-ling WEN; Li YAN; Hua CHENG

    2012-01-01

    To evaluate the effects of aldosterone with or without high sodium intake on blood pressure,myocardial structure and left ventricular function in rats,and to investigate the mechanisms underlying the effects.Methods:Eight-week-old male Sprague-Dawley rats were randomly divided into 3 groups:(1) control (CON) group fed a normal sodium diet,(2) aldosterone (ALD) group receiving aldosterone infusion and a normal sodium diet,and (3) high sodium plus aldosterone (HS-ALD) group receiving 1% NaCl diet in conjunction with aldosterone infusion.Aldosterone was administered through continuously subcutaneous infusion with osmotic minipump at the rate of 0.75 μg/h for 8 weeks.The myocardium structure was observed using transt-horacic echocardiography and transmission electron microscopy.The collagen deposition in left ventricle was evaluated with Masson'strichrome staining.The expression of IL-18,p22phox,and p47phox proteins was examined using Western blot analysis.Results:The systolic blood pressure in the ALD and HS-ALD groups was significantly higher than that in the CON group after 2-week treatment.But the blood pressure showed no significant difference between the HS-ALD and ALD groups.The left ventricular hyper-trophy,myocardial collagen deposition and oxidative stress were predominantly found in the HS-ALD and ALD group.Furthermore,the breakdown of myocardial structure and oxidative stress were more apparent in the HS-ALD group as compared with those in the ALDgroup.Conclusion:Long-term infusion of aldosterone results in hypertension and profibrotic cardiovascular responses in rats fed a normal sodium diet,which were mediated by oxidative stress.High-sodium intake could aggravate myocardial injuries induced by aldosterone.

  12. Changes in serum aldosterone are associated with changes in obesity-related factors in normotensive overweight and obese young adults.

    Science.gov (United States)

    Cooper, Jennifer N; Fried, Linda; Tepper, Ping; Barinas-Mitchell, Emma; Conroy, Molly B; Evans, Rhobert W; Mori Brooks, Maria; Woodard, Genevieve A; Sutton-Tyrrell, Kim

    2013-10-01

    Recent data suggest excess circulating aldosterone promotes cardiometabolic decline. Weight loss may lower aldosterone levels, but little longitudinal data is available in normotensive adults. We aimed to determine whether, independent of changes in sodium excretion, reductions in serum aldosterone are associated with favorable changes in obesity-related factors in normotensive overweight/obese young adults. We studied 285 overweight/obese young adult participants (body mass index ≥ 25 anddiet and physical activity intervention with or without sodium restriction on vascular health. Body weight, serum aldosterone, 24-h sodium and potassium excretion and obesity-related factors were measured at baseline, 6, 12 and 24 months. Weight loss was significant at 6 (7%), 12 (6%) and 24 months (4%; all Pmetabolic syndrome (MetS) at baseline (MetS × weight loss, P=0.04; MetS × change in IMAT, P=0.04). Favorable changes in obesity-related factors are associated with reductions in aldosterone in young adults with no risk factors besides excess weight, an important finding, given aldosterone's emergence as an important cardiometabolic risk factor.

  13. Investigation of the role of aldosterone in hypertension associated with spontaneous pituitary-dependent hyperadrenocorticism in dogs.

    Science.gov (United States)

    Goy-Thollot, I; Péchereau, D; Kéroack, S; Dezempte, J C; Bonnet, J M

    2002-11-01

    The aim of this study was to evaluate the role of aldosterone as an initiating and/or perpetuating factor in hypertension associated with pituitary-dependent hyperadrenocorticism (PDH) in dogs. Thirteen dogs with PDH and 11 healthy control dogs were used. In all dogs, arterial blood pressure and plasma sodium, potassium, basal aldosterone, post-ACTH aldosterone, basal cortisol and post-ACTH cortisol concentrations were measured. The tests were repeated 10 days and three months after the beginning of o,p'-DDD treatment in PDH dogs. In untreated PDH dogs, plasma aldosterone was significantly decreased, whereas cortisol, sodium and arterial blood pressure were significantly increased compared to healthy dogs. Hypertension remained in most treated PDH dogs despite normalisation of cortisol and persistently low aldosterone levels. These results did not demonstrate that aldosterone is involved in the development and perpetuation of hypertension in PDH. However, glucocorticoids seemed to play a major role as an initiating and perpetuating factor in PDH in dogs.

  14. The role of aldosterone receptor blocker therapy in hypertension and heart failure

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    Giuseppina Santese

    2015-09-01

    Full Text Available The aldosterone receptor blocker therapy as an “add-on” to hypotensive therapy is an excellent therapeutic strategy that has proved to be particularly effective in treating refractory hypertension, hypertension with organ damage and overweight hypertensive patients. Aldosterone receptor blockers are extremely useful in inhibiting hormonal activation linked with heart failure: they have cardioprotective effects not only during full-blown heart failure, but also in its early stages, and this effect can be observed even more frequently in heart failures with metabolic syndrome. The use of molecules such as canrenone with a favorable tolerability profile ensures a better tolerability ratio by providing benefits linked to fewer drug interactions, lower incidence of side effects and improved therapy adherence.

  15. Use of computed tomography in diagnosing the cause of primary aldosteronism

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    White, E.A.; Schambelan, M.; Rost, C.R.; Biglieri, E.G.; Moss, A.A.; Korobkin, M.

    1980-12-25

    Computed tomography (CT) was performed in 22 consecutive patients with primary aldosteronism to evaluate the usefulness of this technique in diagnosing and locating aldosterone-producing adenomas. Sixteen patients had severe hypokalemia, hyperaldosteronism, and elevated plasma levels of 18-hydroxycorticosterone suggestive of an adenoma. In 12 of these 16, a unilateral adrenal mass was demonstrated clearly, and in all 11 who had surgery an adenoma was confirmed. In the other four patients in this group, one adrenal gland was normal and the other was either not seen adequately or had minor abnormalities that could not be definitely classified; and adenoma was found in the poorly visualized gland in each of the two patients who had surgery. The remaining six patients, who had milder biochemical abnormalities suggestive of idiopathic hyperaldosteronism, had bilateral adrenal enlargement or normal-appearing glands on scan and were not surgically explored.

  16. Aldosterone and cortisol co-secreting bifunctional adrenal cortical carcinoma: A rare event

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    Puskar Shyam Chowdhury

    2014-01-01

    Full Text Available Adrenocortical carcinoma (ACC co-secreting aldosterone and cortisol is extremely rare. We report the case of a 37-yearold female who presented with paresis and facial puffiness. Evaluation revealed hypertension, hyperglycemia, severe hypokalemia and hyperaldosteronemia with elevated plasma aldosterone to renin ratio (ARR. Urinary free cortisol estimation showed elevated levels. Computed tomography scan revealed a right adrenal mass. Radical adrenalectomy specimen revealed ACC (T3N1. Post-operatively, the patient became normotensive and euglycemic with normalization of urinary cortisol and ARR. This case highlights the need for a complete evaluation in patients of hyperaldosteronism if overlapping symptoms of hypercortisolism are encountered, to avoid post-operative adrenal crisis.

  17. Angiotensin II, Aldosterone, and Anti-Inflammatory Lymphocytes: Interplay and Therapeutic Opportunities

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    Daniel Arthur B. Kasal

    2012-01-01

    Full Text Available Inflammation is recognized as an important factor in the pathophysiology of hypertension, with the renin-angiotensin-aldosterone system (RAAS playing a key role in the disease. Initially described because of its contribution to extracellular fluid and electrolyte homeostasis, the RAAS has been implicated in endothelial dysfunction, vascular remodeling, oxidative stress, proinflammatory cytokine production, and adhesion molecule synthesis by the vascular wall. Both angiotensin II and aldosterone are involved in these systemic effects, activating innate and adaptive immune responses. This paper highlights some aspects connecting RAAS to the hypertensive phenotype, based on experimental and clinical studies, with emphasis on new findings regarding the contribution of an increasingly studied population of T lymphocytes: the T-regulatory lymphocytes. These cells can suppress inflammation and may exert beneficial vascular effects in animal models of hypertension.

  18. Effects of exercise on plasma renin, aldosterone and catecholamines before and after surgery for aortic coarctation.

    Science.gov (United States)

    Sehested, J; Kornerup, H J; Pedersen, E B; Christensen, N J

    1983-01-01

    The pre- and postoperative values of blood pressure, pulse rate, plasma renin activity, plasma aldosterone concentration and circulating catecholamines were studied in a group of 12 patients with uncomplicated aortic coarctation before and after exercise. Mean age of patients studied was 21.5 years. Postoperative studies were carried out on average 204 days after surgery. Following operation, both resting and exercising upper extremity pressures decreased. Six out of the 11 patients still had an abnormally high exercising blood pressure when compared with a normal control group of six persons. Postoperative pulse rates during exercise were significantly higher than pre-operatively (P less than 0.01). No statistically significant differences between pre- and postoperative values, and between patients and normal controls were found in the hormonal studies. This study suggests that the renin-aldosterone-system does not have a major role in the maintenance of the hypertension associated with coarctation of the aorta.

  19. Zero gravity and cardiovascular homeostasis. The relationship between endogenous hyperprolactinemia and plasma aldosterone. Summary report, 1 February 1977--31 January 1978

    Energy Technology Data Exchange (ETDEWEB)

    Haber, E.; Re, R.N.; Kourides, I.A.; Weihl, A.C.; Maloof, F.

    1978-01-31

    Prolactin, thyrotropin, and aldosterone were measured by radioimmunoassay and plasma renin activity by the radioimmunoassay of angiotensin I in normal women before and after the intravenous injection of 200 ..mu..g of thyrotropin-releasing-hormone. Prolactin increased at 15 min following injection of thyrotropin-releasing-hormone. Plasma renin activity was not different from control levels during the first hour following the administration of thyrotropin-releasing-hormone, nor did the plasma aldosterone concentration differ significantly from the control levels during this period. However, with upright posture, an increase in aldosterone and in plasma renin activity was noted, demonstrating a normal capacity to secrete aldosterone. Similarly, no change in aldosterone was seen in 9 patients with primary hypothyroidism given thyrotropin-releasing hormone, despite the fact that the increase in prolactin was greater than normal. These data demonstrate that acutely or chronically elevated serum prolactin levels do not result in increased plasma aldosterone levels in humans.

  20. mPGES-1 deletion impairs aldosterone escape and enhances sodium appetite

    OpenAIRE

    Jia, Zhanjun; Aoyagi, Toshinori; Kohan, Donald E.; Yang, Tianxin

    2010-01-01

    Aldosterone (Aldo) is a major sodium-retaining hormone that reduces renal sodium excretion and also stimulates sodium appetite. In the face of excess Aldo, the sodium-retaining action of this steroid is overridden by an adaptive regulatory mechanism, a phenomenon termed Aldo escape. The underlying mechanism of this phenomenon is not well defined but appeared to involve a number of natriuretic factors such prostaglandins (PGs). Here, we investigated the role of microsomal prostaglandin E synth...

  1. Association of KCNJ5 gene missense mutations with aldosterone-producing adenoma and primary hyperaldosteronism

    Institute of Scientific and Technical Information of China (English)

    邵丹

    2013-01-01

    Objective To detect the KCNJ5 gene variations in aldosterone-producing adenoma (APA) with primary hyperaldosteronism (PA) ,and to investigate the association of the KCNJ5 gene missense mutations with APA and PA.Methods A total of 46 APA tumors and their clinical characteristics were collected from Hypertension Center of the People’s Hospital of Xinjiang Uygur Autonomous Region,and all the tumors were confirmed by pathology.

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

    Directory of Open Access Journals (Sweden)

    M. Kourosh Arami

    2004-04-01

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

  3. A Rare Cause of Hypokalemia: Aldosterone-Secreting Adrenocortical Carcinoma Dear Editor,

    Directory of Open Access Journals (Sweden)

    Ethem Turgay Cerit

    2014-03-01

    Full Text Available Adrenocortical carcinoma (ACC is a rare malignancy accounting for 0.05-0.2% of all cancers (1. Determinants of prognosis are the stage of disease and completeness of resection(2. Approximately 60% of ACCs are hormonally active and glucocorticoids and/or androgens are most frequently over-secreted (2. Rapid development of signs and symptoms of Cushing’s syndrome is the most frequent presentation (3. Aldosterone-secreting ACC is extremely uncommon, comprising 0% to 7% of all functioning ACCs and presents with severe hypertension and profound hypokalemia (4. Here we report a case diagnosed as aldosterone producing adrenocortical carcinoma presented with severe hypokalemia and hypertension. A 32-year-old man referred to our instution because of pain and marked weakness especially in his lower extremities for 2 months. On admission his blood pressure was 180 mmHg systolic and 110 mmHg diastolic. Laboratory investigation revealed severe hypokalemia (2.6 mmol/l (normal: 3.5-5.5 mmol/l, elevated serum aldosterone (39.0 ng/dl (normal: 0.8-13 ng/dl with suppressed plasma renin activity (0.07 ng/ml/h. Serum sodium level was 142 mmol/l (normal: 135-146 mmol/l. Serum aldosterone level was not supressed (38.2 ng/dl after saline infusion test. Serum dehydroepiandrosterone sulfate (DHEA-SO4 was 150 mcg/dl (normal: 80-560, Δ4-androstenedione was 1.91 ng/ml (normal: 0.5-4.8 and total testosterone was 447.3 ng/dl (normal: 229.8-799.8 (Table 1. Suppressed renin levels, increased aldosterone levels with an aldosterone/renin ratio >30 were suggestive findings of aldosterone-producing adenoma of the adrenal gland or bilateral adrenal hyperplasia. Computed tomography demonstrated a large (4.6 cm left-sided adrenal tumour which is heterogeneous and has lobulated margin without a contrasting pattern of adenoma (Figure 1. 24-h urinary catecholamines and low-dose dexamethasone-suppressed plasma cortisol concentrations were all normal. At surgery, an adrenal mass (70

  4. Mild Adrenal Steroidogenic Defects and ACTH-Dependent Aldosterone Secretion in High Blood Pressure: Preliminary Evidence

    Directory of Open Access Journals (Sweden)

    João Martin Martins

    2014-01-01

    Full Text Available Introduction. Adrenal glands play a major role in the control of blood pressure and mild defects of steroidogenesis and/or inappropriate control of mineralocorticoid production have been reported in high blood pressure (HBP. Patients and Methods. We used a specific protocol for the evaluation of 100 consecutive patients with inappropriate or recent onset HBP. Specific methods were used to confirm HBP and to diagnose secondary forms of HBP. In addition we tested adrenal steroidogenesis with the common cosyntropin test, modified to include the simultaneous measurement of renin and aldosterone besides 17-hydroxyprogesterone (17OHP and 11-deoxycortisol (S. Results. Secondary forms of HBP were diagnosed in 32 patients, including 14 patients with primary hyperaldosteronism (PA (14% and 10 patients with pheochromocytoma (10%. Mild defects of the 21-hydroxylase (21OHD and 11-hydroxylase (11OHD enzymes were common (42%. ACTH-dependent aldosterone secretion was found in most patients (54% and characteristically in those with mild defects of adrenal steroidogenesis (>60%, PA (>75%, and otherwise in patients with apparent essential HBP (EHBP (32%. Discussion. Mild defects of adrenal steroidogenesis are common in patients with HBP, occurring in almost half of the patients. In those patients as well as in patients with apparent EHBP, aldosterone secretion is commonly dependent on ACTH.

  5. Aldosterone deficiency after unilateral adrenalectomy for Conn’s syndrome: a case report and literature review

    Science.gov (United States)

    Yorke, Ekua; Stafford, Sara; Holmes, Daniel; Sheth, Sachiv; Melck, Adrienne

    2015-01-01

    Introduction Approximately 35% of cases of Conn’s syndrome (primary aldosteronism) result from a solitary functioning adrenal adenoma, and these patients are best managed by adrenalectomy. Postoperative hypoaldosteronism after unilateral adrenalectomy is uncommon. Case presentation We present a case and literature review of hypoaldosteronism after unilateral adrenalectomy for Conn’s syndrome, which demonstrates the insidious and sometimes delayed presentation. Discussion In this clinical case we summarize the previously published cases of post-adrenalectomy hypoaldosteronism based on a PUBMED and EBSCOhost search of all peer-reviewed publications (original articles and reviews) on this topic. A few cases of aldosterone insufficiency post-adrenalectomy for Conn’s syndrome were identified. The etiological factors for prolonged selective suppression of aldosterone secretion after unilateral adrenalectomy remain unclear. Conclusion It is important to be aware of the risk of postoperative hypoaldosteronism in this patient population. Close postoperative follow-up is necessary and strongly recommended, especially in patients with certain risk factors. Patients may need mineralocorticoid supplementation during this period. PMID:25604311

  6. 不同体位血浆肾素和醛固酮及其比值诊断原发性醛固酮增多症的价值%Value of plasma renin, aldosterone and aldosterone to renin ratio in different positions to diagnosing primary aldosteronism

    Institute of Scientific and Technical Information of China (English)

    张玉杰; 李南方; 张菊红; 姚晓光; 李变

    2013-01-01

    Objective To discuss the values of plasma renin activity,plasma aldosterone concentration and aldosterone to renin ratio (ARR) in three positions (upright,sitting and supine positions) to diagnosing primary aldosteronism.Methods A total of 108 patients were detected plasma renin activity and plasma aldosterone concentration in three positions by using radioimmunity assay,and received intravenous saline load test.The ROC curves of plasma renin activity,plasma aldosterone concentration and ARR were drawn respectively on the basis of the intravenous saline load test results as diagnostic standard for primary aldosteronism.Results The AUC values of plasma aldosterone concentration and ARR in supine position were the biggest,indicating a high diagnostic accuracy for primary aldosteronism.The optimum cut-off points of ARR and plasma aldosterone concentration in supine position were 118.3 hours and 53 ng/L,with the coincidences of 57.1 % and 41.1% with intravenous saline load test to diagnose primary aldosteronism.The sensitivity,specificity and Youden index of the combination of ARR ≥ 118.3 hours with plasma aldosterone concentration ≥53 ng/L in supine position were 47.6%,94.1% and 0.471,with the coincident rate of 85.7 %.Conclusion In the patients unable to undergo intravenous saline load test,ARR (≥118.3 hours) combined with plasma aldosterone concentration (≥ 53 ng/L in supine position could improve the diagnosis rate of primary aldosteronism.%目的 探讨立、坐、卧位血浆肾素、醛固酮及醛固酮/肾素比值(aldosterone to renin ratio,ARR)对原发性醛固酮增多症(primary aldosteronism,PA)的诊断价值.方法 采用放射免疫法检测108例高血压患者立、坐、卧位血浆肾素活性及醛固酮水平,并行静脉盐水负荷试验;以静脉盐水负荷试验为PA的诊断标准,分别绘制肾素、醛固酮及ARR的ROC曲线.结果 卧位醛固酮的AUC最大,卧位ARR的AUC最大,诊断PA的准确性较高;

  7. Ingestion of sodium citrate suppresses aldosterone level in blood at rest and during exercise.

    Science.gov (United States)

    Oöpik, Vahur; Timpmann, Saima; Hackney, Anthony C; Kadak, Kadri; Medijainen, Luule; Karelson, Kalle

    2010-06-01

    The purpose of this study was to determine if the ingestion of sodium citrate (CIT) alters blood levels of fluid and electrolyte regulatory hormones at rest and during exercise. Using a randomized, double-blinded, crossover design, 13 young, male well-trained runners performed continuous incremental running tests to volitional exhaustion on a treadmill 2 h after ingestion of 0.5 g.kg-1 body mass of CIT or placebo (PLC) in 1000 mL of solution. These trials were separated by 2 weeks. Baseline (before ingestion) aldosterone concentration did not differ between the 2 trials; however, it was 36.5% (p = 0.003) lower in the CIT trial compared with the PLC trial before the running test (i.e., after ingestion). The extent of the running-induced increase in aldosterone was 33% (p = 0.009) smaller in the CIT trial. There were no between-trial differences in the levels of adrenocorticotropic hormone, N-terminal pro-B-type natriuretic peptide, or renin activity at any stage of the study. However, a greater relative increase in plasma volume (mean +/- SD, 6.41% +/- 3.78% vs. 4.08% +/- 3.33%; p = 0.042) was observed after administering the CIT compared with the PLC drink. Serum Na+ concentration increased (by 3.1 +/- 1.2 mmol.L-1; p < 0.0001) after ingestion of the CIT but not the PLC drink. A higher Na+ level was observed in the CIT trial than in the PLC trial (142.4 +/- 1.6 vs. 139.3 +/- 1.4 mmol.L-1, p = 0.00001) after completion of the run. In conclusion, pre-exercise ingestion of CIT induces a decrease in serum aldosterone concentration in the resting condition and a blunting of the aldosterone response during incremental running exercise to volitional exhaustion. The observed effect of CIT on the serum aldosterone level may be mediated by an acute increase in plasma volume and serum Na+ concentration alterations.

  8. Effect of age on aldosterone/renin ratio (ARR) and comparison of screening accuracy of ARR plus elevated serum aldosterone concentration for primary aldosteronism screening in different age groups.

    Science.gov (United States)

    Yin, Guoshu; Zhang, Shaoling; Yan, Li; Wu, Muchao; Xu, Mingtong; Li, Feng; Cheng, Hua

    2012-08-01

    The serum aldosterone concentration (SAC)/plasma renin activity (PRA) ratio (ARR) is considered a useful screening test in the differential diagnosis of essential hypertension (EH) and primary aldosteronism (PA). The purpose of this study is to investigate the effect of age on ARR and compare the screening accuracy of ARR plus elevated SAC for PA screening in different age groups. Thirty-nine patients with PA, 274 patients with EH, and 153 healthy volunteers were recruited. Blood was sampled for SAC and PRA measuring under keeping upright posture for 1 h. Levels of SAC, PRA, and ARR were compared at different ages range for the respective three groups of subjects. The screening accuracy of ARR plus elevated SAC was compared in different age groups and PA patients served as the same positive subjects. In the EH group, logarithmically transformed ARR (Log-ARR) increased with advancing age and reached its peak in the ≥ 60 years group; in the normotensives group, Log-ARR reached its peak in the 40-49 years group and slightly declined with advancing age. In the PA group, Log-ARR was not age dependent. Screening accuracy increased when combined index of ARR and SAC was used in the ≥ 40 years group but not in the <40 years group. Although the number of EH patients with elevated ARR increased with advancing age, but the screening accuracy and cutoff values of ARR were not affected by age. Using the combined index of ARR and SAC increased the screening accuracy for the patients older than 40 years, but not necessary for the patients younger than 40 years.

  9. The clinical significance of aldosterone synthase deficiency: report of a novel mutation in the CYP11B2 gene

    Science.gov (United States)

    2014-01-01

    Background Aldosterone synthase (CYP11B2) deficiency is a rare autosomal recessive disorder, usually presenting with severe salt-wasting in infancy or stress-induced hyperkalaemia and postural hypotension in adulthood. Neonatal screening for congenital adrenal hyperplasia, another cause of salt wasting, using 17-hydroxyprogesterone measurement would fail to detect aldosterone synthase deficiency, a diagnosis which may be missed until the patient presents with salt-wasting crisis. Due to this potential life-threatening risk, comprehensive hormonal investigation followed by genetic confirmation for suspected patients would facilitate clinical management of the patient and assessment of the genetic implication in their offspring. Case presentation We describe a 33-year old Chinese man who presented in infancy with life-threatening hyponatraemia and failure to thrive, but remained asymptomatic on fludrocortisone since. Chromosomal analysis confirmed a normal male karyotype of 46, XY. Plasma steroid profile showed high plasma renin activity, low aldosterone level, and elevated 18-hydroxycorticosterone, compatible with type 2 aldosterone synthase deficiency. The patient was heterozygous for a novel CYP11B2 mutation: c.977C > A (p.Thr326Lys) in exon 3. He also carried a heterozygous mutation c.523_525delAAG (p.Lys175del) in exon 6, a known pathogenic mutation causing aldosterone synthase deficiency. Sequencing of CYP11B2 in his parents demonstrated that the mother was heterozygous for c.977C > A, and the father was heterozygous for c.523_525delAAG. Conclusion Although a rare cause of hyperreninaemic hypoaldosteronism, aldosterone synthase deficiency should be suspected and the diagnosis sought in patients who present with life-threatening salt-wasting in infancy, as it has a good long-term prognosis when adequate fludrocortisone replacement is instituted. To our knowledge, this is the first Chinese patient in which the molecular basis of aldosterone synthase

  10. SY 03-3 OVERVIEW OF SOMATIC MUTATIONS AND EPIGENETIC REGULATION OF ALDOSTERONE PRODUCING ADENOMA (APA).

    Science.gov (United States)

    Umemura, Satoshi

    2016-09-01

    Primary aldosteronism (PA) is a heterogeneous group of disorders including both sporadic and familial forms (familial hyperaldosteronism type I, II and III). PA is the most frequent endocrine cause of secondary hypertension and associated with a higher rate of cardiovascular complications, compared with essential hypertension.Here I review the recent progress in understanding of the genetic and molecular mechanisms leading to autonomous aldosterone production in PA.Systematic screening detects primary aldosteronism in 5 to 10% of all patients with hypertension and in approximately 20% of patients with resistant hypertension. A unilateral APA is the most common curable cause of hypertension. Early detection of an APA is important both to cure of hypertension by means of adenoma removal and to prevent the onset of resistant hypertension and the risk of long-term cardiovascular complications, such as left ventricular hypertrophy, coronary artery disease, myocardial infarction, heart failure, and atrial fibrillation. (Hypertens 2013; 62: 331)(1) Novel somatic mutations in APARecent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA. Pathogenic mechanisms of APA by the somatic mutation are as follows.The majority of the GIRK4 APA mutations (KCNJ5) lie in or within the close proximity of the ion selectivity filter of the K+ channel and result in the indiscriminate conductance of Na+ that causes membrane depolarization, Ca2+ influx, and increased aldosterone biosynthesis.Mutations in the Na+/K+- ATPase 1 (ATP1A1) produce a decrease in K+ binding that results in the reduced import of K+ and export of Na+ and also causes cell depolarization. This in turn results in the opening of voltage- gated Ca2+-channels.In contrast, the Ca2+-ATPase mutations (ATP2B3) were proposed to affect the clearance of cytoplasmic calcium ions. The net result of mutations in both ATPases is therefore likely to cause

  11. Synthesis of potential mescaline antagonists.

    Science.gov (United States)

    DeSantis, F; Nieforth, K A

    1976-10-01

    1-[2-(3,4,5-Trimethoxyphenyl)ethyl]-3-pyrroline, 2-(3,4,5-trimethoxybenzyl)-1,2,3,6-tetrahydropyridine, N-n-propylmescaline, N-cyclopropylmethylmescaline, and N-allylmescaline were synthesized as potential mescaline antagonists. The ability of these compounds to antagonize mescaline-induced disruption of swim behavior is also given.

  12. Excitatory amino acid receptor antagonists

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B

    1997-01-01

    We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation......)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments......, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation...

  13. DEVELOPMENT OF NEW LHRH ANTAGONISTS

    Institute of Scientific and Technical Information of China (English)

    PENGDun-Ren; XIAOShao-Bo

    1989-01-01

    An ideal antagonist of LHRH is one which can act on the pitutary to inhibit LHRH-stimulatod LH / FSH secretion by competitive occupying the LHRH receptor in the pitutary gland. Its action should be very specific, fast and highly effective, the durations

  14. The renal thiazide-sensitive Na-Cl cotransporter as mediator of the aldosterone-escape phenomenon.

    Science.gov (United States)

    Wang, X Y; Masilamani, S; Nielsen, J; Kwon, T H; Brooks, H L; Nielsen, S; Knepper, M A

    2001-07-01

    The kidneys "escape" from the Na-retaining effects of aldosterone when circulating levels of aldosterone are inappropriately elevated in the setting of normal or expanded extracellular fluid volume, e.g., in primary aldosteronism. Using a targeted proteomics approach, we screened renal protein extracts with rabbit polyclonal antibodies directed to each of the major Na transporters expressed along the nephron to determine whether escape from aldosterone-mediated Na retention is associated with decreased abundance of one or more of renal Na transporters. The analysis revealed that the renal abundance of the thiazide-sensitive Na-Cl cotransporter (NCC) was profoundly and selectively decreased. None of the other apical solute-coupled Na transporters displayed decreases in abundance, nor were the total abundances of the three ENaC subunits significantly altered. Immunocytochemistry showed a strong decrease in NCC labeling in distal convoluted tubules of aldosterone-escape rats with no change in the cellular distribution of NCC. Ribonuclease protection assays (RPAs) revealed that the decrease in NCC protein abundance was not associated with altered NCC mRNA abundance. Thus, the thiazide-sensitive Na-Cl cotransporter of the distal convoluted tubule appears to be the chief molecular target for regulatory processes responsible for mineralocorticoid escape, decreasing in abundance via a posttranscriptional mechanism.

  15. Inappropriately low aldosterone concentrations in adults with AIDS-related diarrhoea in Zambia: a study of response to fluid challenge

    Directory of Open Access Journals (Sweden)

    Lumayi Ruth

    2008-04-01

    Full Text Available Abstract Background Chronic diarrhoea is one of the most debilitating consequences of HIV infection in sub-Saharan Africa and it carries a high mortality rate. We report unexpectedly low concentrations of circulating aldosterone in 12 patients (6 men, 6 women in the University Teaching Hospital, Lusaka, who all had diarrhoea for over one month. Changes in serum electrolytes, blood pressure, Karnofsky score and serum aldosterone concentration were being monitored during a short study of responses to saline infusion (3 litres/24 h over 72 hours. Findings At baseline, 9/12 (75% of the patients were hyponatraemic, 10/11 (91% were hypokalaemic, and 6/12 (50% had undetectable aldosterone concentrations. Blood pressure and Karnofsky score rose and creatinine concentration fell in response to the infusion. Conclusion Circulating aldosterone concentrations were inappropriately low and complicate the profound electrolyte deficiencies resulting from chronic diarrhoea. Management of these deficiencies needs to be more aggressive than is currently practised and consideration should be given to a formal clinical trial of mineralocorticoid replacement in these severely ill patients. If the inappropriately low aldosterone reflects a general adrenal failure, it may explain a considerable proportion of the high mortality seen both before and after initiation of anti-retroviral therapy.

  16. Age dependence of the levels of plasma norepinephrine, aldosterone, renin activity and urinary vanillylmandelic acid in normal and essential hypertensives.

    Science.gov (United States)

    Abd-Allah, Nadia M; Hassan, Fayeza H; Esmat, Amr Y; Hammad, Somaya A

    2004-01-01

    In the present study the upper reference limits (URLs) for resting plasma norepinephrine, epinephrine, serum aldosterone, plasma renin activity, aldosterone/renin activity ratio, as well as urinary vanillylmandelic acid in healthy Egyptian normotensive subjects over a range of ages (5-60 yr) were established. There was a significant age effect on plasma norepinephrine, UVMA, serum aldosterone and PRA, whereas a single URL for plasma epinephrine level is satisfactory. In uncomplicated untreated essential hypertensive subjects (5-60 yr), the average prevalence of elevation in the plasma norepinephrine, epinephrine and urinary vanillylmandelic acid above their corresponding URLs was 85.10, 62.15 and 83.20%, respectively. This suggests that elevation in plasma catecholamine concentrations is more likely a common consequence than playing a possible role in the pathogenesis of hypertension, supported by insignificant correlation coefficients between the plasma catecholamine levels and resting systolic and diastolic blood pressure values (SBP & DBP) in all hypertensive age groups. Primary hyperaldosteronism was not detected among the normokalemic essential hypertensives at any age using aldosterone/plasma renin activity ratio as a primary screening method. In the present study, 7 statistically significant positive coefficient correlations are reported for SBP or DBP values with UVMA levels in hypertensive children and adolescents, serum aldosterone in old hypertensives, and PRA in adult hypertensives.

  17. Two novel mutations of the CYP11B2 gene in a Japanese patient with aldosterone deficiency type 1.

    Science.gov (United States)

    Kondo, Eisuke; Nakamura, Akie; Homma, Keiko; Hasegawa, Tomonobu; Yamaguchi, Takeshi; Narugami, Masahiko; Hattori, Tetsuo; Aoyagi, Hayato; Ishizu, Katsura; Tajima, Toshihiro

    2013-01-01

    Isolated hypoaldosteronism is a rare and occasionally life-threatening cause of salt wasting in infancy. A 2-month-old Japanese boy of unrelated parents was examined for failure to thrive and poor weight gain. Laboratory findings were hyponatremia, hyperkalemia, high plasma renin and low aldosterone levels. Spot urine analysis by gas chromatography-mass spectrometry (GC-MS) showed that urinary excretion of corticosterone metabolites was elevated. Whereas excretion of 18-hydroxycortricosterone metabolites was within the normal range, excretion of aldosterone metabolites was undetectable. The patient was therefore suspected to have aldosterone synthase deficiency type 1. Sequence analysis of CYP11B2, the gene encoding aldosterone synthase (CYP11B2), showed that the patient was a compound heterozygote for c.168G>A, p.W56X in exon 1 and c.1149C>T, p.R384X in exon 7. p.W56X was inherited from his mother and p.R384X was from his father. Since both alleles contain nonsense mutations, a lack of CYP11B2 activity was speculated to cause his condition. To our knowledge, this is the first Japanese patient in which the molecular basis of aldosterone synthase deficiency type 1 has been clarified. This case also indicates that spot urinary steroid analysis is useful for diagnosis.

  18. One-hour upright posture is an ideal position for serum aldosterone concentration and plasma renin activity measuring on primary aldosteronism screening.

    Science.gov (United States)

    Yin, G; Zhang, S; Yan, L; Wu, M; Xu, M; Li, F; Cheng, H

    2012-07-01

    The serum aldosterone concentration (SAC) to plasma renin activity (PRA) ratio (ARR) is considered a useful screening test in the differential diagnosis of essential hypertension (EH) and primary aldosteronism (PA). The purpose of this study is to investigate the variation of ARR and compare the screening efficiency of it under different postures.37 patients with PA and 92 patients with EH were recruited in this study. Blood was sampled for measuring SAC and PRA under conditions of overnight recumbency, keeping upright posture for 1 h, 2 h and 4 h. The variation and screening efficiency of ARR under these conditions were compared according to repeated measured ANOVA and ROC curve analysis.In the EH group, ARR measured under recumbency posture was higher than those measured under keeping upright posture for 1 h and 2 h. In the PA group, there is no statistical difference for ARR between any 2 postures. AUCs of ARR measured under 4 conditions were 0.976, 0.995, 0.988, and 0.974 respectively. Cutoff values were ranging from 24.75 ng/dl per ng/ml/h under keeping upright for 2 h to 69.19 ng/dl per ng/ml/h under overnight recumbercy. ARR measured under keeping upright posture for 1 h produced the best characteristic of screening efficiency.Keeping upright posture for 1 h was the ideal position for ARR measuring and using a cutoff value of 35.90 ng/dl per ng/ml/h will have a sensitivity and specificity of 100.00% and 92.30% respectively.

  19. Mizoribine ameliorates renal injury and hypertension along with the attenuation of renal caspase-1 expression in aldosterone-salt-treated rats.

    Directory of Open Access Journals (Sweden)

    Toshiki Doi

    Full Text Available Aldosterone-salt treatment induces not only hypertension but also extensive inflammation that contributes to fibrosis in the rat kidney. However, the mechanism underlying aldosterone-salt-induced renal inflammation remains unclear. Pyroptosis has recently been identified as a new type of cell death that is accompanied by the activation of inflammatory cytokines. We hypothesized that aldosterone-salt treatment could induce inflammation through pyroptosis and that mizoribine, an effective immunosuppressant, would ameliorate the renal inflammation that would otherwise cause renal fibrosis. Ten days after recovery from left uninephrectomy, rats were given drinking water with 1% sodium chloride. The animals were divided into three groups (n = 7 per group: (1 vehicle infusion group, (2 aldosterone infusion group, or (3 aldosterone infusion plus oral mizoribine group. Aldosterone-salt treatment increased the expression of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 and caspase-1, and also increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. However, the oral administration of mizoribine attenuated these alterations. Furthermore, mizoribine inhibited hypertension and renal fibrosis, and also attenuated the aldosterone-induced expression of serum/glucocorticoid-regulated kinase and α epithelial sodium channel. These results suggest that caspase-1 activation plays an important role in the development of inflammation induced by aldosterone-salt treatment and that it functions as an anti-inflammatory strategy that protects against renal injury and hypertension.

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

    Institute of Scientific and Technical Information of China (English)

    Yan-Huan Feng; Ping Fu

    2016-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2007-01-01

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

  2. Diagnostic Role of Captopril Challenge Test in Korean Subjects with High Aldosterone-to-Renin Ratios

    Directory of Open Access Journals (Sweden)

    Jung Hee Kim

    2016-06-01

    Full Text Available BackgroundDiagnosis of primary aldosteronism (PA begins with aldosterone-to-renin ratio (ARR measurement followed by confirmative tests. However, the ARR has high false positive rates which led to unnecessary confirmatory tests. Captopril challenge test (CCT has been used as one of confirmatory tests, but the accuracy of it in the diagnosis of PA is still controversial. We aimed to examine the clinical efficacy of CCT as a post-screening test in PA.MethodsIn a prospective study, we enrolled subjects with suspected PA who had hypertension and ARR >20 (ng/dL/(ng/mL/hr. Sixty-four patients who underwent both the saline infusion test and the CCT were included.ResultsThe diagnostic performance of plasma aldosterone concentration (PAC post-CCT was greater than that of ARR post-CCT and ARR pre-CCT in PA (area under the curve=0.956, 0.797, and 0.748, respectively; P=0.001. A cut-off value of 13 ng/dL showed the highest diagnostic odds ratio considering PAC post-CCT at 60 and 90 minutes. A PAC post-CCT of 19 ng/dL had a specificity of 100%, which can be used as a cut-off value for the confirmative test. Determining the diagnostic performance of PAC post-CCT at 90 minutes was sufficient for PA diagnosis. Subjects with PAC post-CCT at 90 minutes <13 ng/dL are less likely to have PA, and those with PAC post-CCT at 90 minutes ≥13 but <19 ng/dL should undergo secondary confirmatory tests.ConclusionThe CCT test may be a reliable post-screening test to avoid the hospitalization in the setting of falsely elevated ARR screening tests.

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

    Directory of Open Access Journals (Sweden)

    S.R.S. Freitas

    2007-03-01

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

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

    Science.gov (United States)

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

    2013-12-01

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

  5. Reduced plasma aldosterone concentrations in randomly selected patients with insulin-dependent diabetes mellitus.

    LENUS (Irish Health Repository)

    Cronin, C C

    2012-02-03

    Abnormalities of the renin-angiotensin system have been reported in patients with diabetes mellitus and with diabetic complications. In this study, plasma concentrations of prorenin, renin, and aldosterone were measured in a stratified random sample of 110 insulin-dependent (Type 1) diabetic patients attending our outpatient clinic. Fifty-four age- and sex-matched control subjects were also examined. Plasma prorenin concentration was higher in patients without complications than in control subjects when upright (geometric mean (95% confidence intervals (CI): 75.9 (55.0-105.6) vs 45.1 (31.6-64.3) mU I-1, p < 0.05). There was no difference in plasma prorenin concentration between patients without and with microalbuminuria and between patients without and with background retinopathy. Plasma renin concentration, both when supine and upright, was similar in control subjects, in patients without complications, and in patients with varying degrees of diabetic microangiopathy. Plasma aldosterone was suppressed in patients without complications in comparison to control subjects (74 (58-95) vs 167 (140-199) ng I-1, p < 0.001) and was also suppressed in patients with microvascular disease. Plasma potassium was significantly higher in patients than in control subjects (mean +\\/- standard deviation: 4.10 +\\/- 0.36 vs 3.89 +\\/- 0.26 mmol I-1; p < 0.001) and plasma sodium was significantly lower (138 +\\/- 4 vs 140 +\\/- 2 mmol I-1; p < 0.001). We conclude that plasma prorenin is not a useful early marker for diabetic microvascular disease. Despite apparently normal plasma renin concentrations, plasma aldosterone is suppressed in insulin-dependent diabetic patients.

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

    Directory of Open Access Journals (Sweden)

    Yan-Huan Feng

    2016-01-01

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

  7. The first laparoscopic resection of an aldosterone-secreting adrenocortical oncocytoma in a child

    Directory of Open Access Journals (Sweden)

    Melih Akin

    2014-09-01

    Full Text Available Oncocytomas of the adrenal cortex are usually benign and nonfunctional, consisting of oncocytes in which the cytoplasm becomes eosinophilic due to the accumulation of abnormal mitochondria. Oncocytomas can exist in many organs and are frequently found in the salivary gland, kidneys, thyroid gland, parathyroid gland, and hypophysis. Functioning oncocytomas are very rarely observed in children, and no more than ten cases have been reported in the literature. Here, we present the first report of laparoscopic excision of an aldosterone-secreting adrenocortical oncocytoma in a child.

  8. 详释醛固酮逃逸%Interpretation of Aldosterone Escape

    Institute of Scientific and Technical Information of China (English)

    梁昊; 周小青

    2012-01-01

    从“醛固酮逃逸”的概念入手,结合国内外多篇文献,全面解读其含义,并提出了相应的修改意见,以便能够规范应用。%Although the term "aldosterone escape" has been used for years, its concept is not explicit. Hence, it's misused by people, which misled basic research and clinical practice. We interpret the meaning in detail based on related literatures, and put forward some modification suggestions for standardized use.

  9. Mineralocorticoid receptor in the NTS stimulates saline intake during fourth ventricular infusions of aldosterone.

    Science.gov (United States)

    Koneru, Bhuvaneswari; Bathina, Chandra Sekhar; Cherry, Brandon H; Mifflin, Steve W

    2014-01-01

    The purpose of this study was to determine whether neurons within the nucleus tractus solitarius (NTS) that express the mineralocorticoid receptor (MR) play a role in aldosterone stimulation of salt intake. Adult Wistar-Kyoto (WKY) rats received microinjections into the NTS of a short-hairpin RNA (shRNA) for the MR, to site specifically reduce levels of the MR by RNA interference (shRNA; n = 9) or scrambled RNA as a control (scRNA; n = 8). After injection of the viral construct, aldosterone-filled osmotic minipumps were implanted subcutaneously and connected to a cannula extending into the fourth ventricle to infuse aldosterone at a rate of 25 ng/h. Before and after surgeries, rats had ad libitum access to normal sodium (0.26%) rat chow and two graduated drinking bottles filled with either distilled water or 0.3 M NaCl. Before the surgeries, basal saline intake was 1.6 ± 0.6 ml in the scRNA group and 1.56 ± 0.6 ml in the shRNA group. Twenty-four days postsurgery, saline intake was elevated to a greater extent in the scRNA group (5.9 ± 1.07 ml) than in the shRNA group (2.41 ± 0.6 ml). Post mortem immunohistochemistry revealed a significant reduction in the number of NTS neurons exhibiting immunoreactivity for MR in shRNA-injected rats (23 ± 1 cells/section) versus scRNA-injected rats (33 ± 2 cells/section; P = 0.008). shRNA did not alter the level of 11-β-hydroxysteroid dehydrogenase type II (HSD2) protein in the NTS as judged by the number of HSD2 immunoreactive neurons. These results suggest that fourth ventricular infusions of aldosterone stimulate saline intake, and that this stimulation is at least in part mediated by hindbrain NTS neurons that express MR.

  10. 局部醛固酮系统与糖尿病肾病%Local aldosterone system and diabetic nephropathy

    Institute of Scientific and Technical Information of China (English)

    杨珊; 杜超; 周波

    2012-01-01

    肾上腺以外组织局部醛固酮合酶(CYP11B2)及盐皮质激素受体(MR)的表达提示了局部醛固酮系统的形成,研究证实肾脏内存在局部醛固酮系统,在肾脏足细胞、系膜细胞和肾小管上皮细胞内存在局部醛固酮系统的全部组分.高血糖可激活肾脏局部醛固酮系统,进而通过炎性反应、氧化应激、细胞外基质积聚、细胞凋亡和肾小管间质转分化等方式加速糖尿病肾病的发生与发展.MR拮抗剂和CYP11 B2抑制剂均可阻断局部醛固酮系统,这将是糖尿病肾病治疗的一个新方向.%The expression of aldosterone synthase(CYP11B2) and mineralocorticoid receptor(MR) in extraadrenal tissues suggests the formation of local aldosterone system.Studies have confirmed the presence of local aldosterone systems in kidney.All the essential components of an aldosterone system could be found in renal podocytes,mesangial cells and renal tubular epithelial cells.Hyperglycemia could activate these renal aldosterone systems,which may accelerate the development and progression of diabetic nephropathy (DN) via inflammatory response,oxidative stress,extracellular matrix accumulation,cell apoptosis and renal tubular mesenchymal transdifferentiation.Both MR antagonsits and CYP11B2 inhibitors could block local aldosterone system,this may be a new direction in the treatment of DN.

  11. Effect of atrial natriuretic peptide on potassium-stimulated aldosterone secretion: potential relevance to hypoaldosteronism in man.

    Science.gov (United States)

    Clark, B A; Brown, R S; Epstein, F H

    1992-08-01

    Atrial natriuretic peptide (ANP) has been shown to suppress aldosterone secretion under certain circumstances, although the physiological significance of this is uncertain. We wondered if ANP would suppress potassium-stimulated aldosterone secretion in man and, if so, whether we might find high circulating levels of ANP in patients with the syndrome of acquired hypoaldosteronism. We studied seven healthy young subjects under two conditions: 1) infusion of KCl (0.5 mmol/kg) over 45 min, and 2) KCl infused with ANP (0.01 microgram/kg.min) for 60 min. We also evaluated ANP levels in eight elderly subjects with the syndrome of acquired hypoaldosteronism, as defined by hyperkalemia (mean serum K+, 5.3 +/- 0.1 mmol/L) associated with inappropriately low aldosterone levels (216 +/- 50 pmol/L). In the normal subjects, ANP almost completely suppressed the aldosterone response to KCl infusion (P less than 0.001, by analysis of variance) despite a similar rise in the serum potassium level with KCl alone (0.70 +/- 0.07 mmol/L) and KCl plus ANP (0.75 +/- 0.09 mmol/L). PRA fell slightly during KCl plus ANP treatment, but did not change during the infusion of KCl alone. ANP levels were approximately 800 pmol/L during the ANP infusion studies. Endogenous ANP levels in the hyperkalemic patients with hypoaldosteronism were markedly elevated at 1186 +/- 340 pmol/L (compared to 93 +/- 10 pmol/L in healthy elderly controls), a level that would be capable of suppressing the potassium-mediated aldosterone response. Exogenous infusion of ANP suppressed the aldosterone response to hyperkalemia, and ANP levels were found to be markedly elevated in a group of patients with hyperkalemia and hypoaldosteronism. We suggest that ANP may contribute to clinically significant hypoaldosteronism and hyperkalemia in the syndrome of acquired hypoaldosteronism.

  12. Selective hypoaldosteronism due to combined defects of the conversion from inactive renin to active renin and the aldosterone biosynthesis from corticosterone.

    Science.gov (United States)

    Muto, S; Akai, Y; Ono, S; Kusano, E; Asano, Y

    2001-07-01

    A 24-year-old Japanese woman with IgA nephropathy exhibited a decreased serum aldosterone level with normal plasma renin activity after toxemia of pregnancy. Our studies revealed selective hypoaldosteronism with normal adrenoglucocorticoid functions. Levels of serum corticosterone and deoxycorticosterone were normal. Resting plasma renin activity was normal, and plasma levels of total and inactive renin were increased. Rapid ACTH administration failed to stimulate any secretion of aldosterone, whereas it adequately increased serum cortisol, deoxycorticosterone, and corticosterone concentrations. Responses of both plasma renin activity and serum aldosterone level to the furosemide-posture challenge were blunted. Angiotensin II also failed to stimulate any secretion of aldosterone despite a progressive rise in blood pressure and an appropriate increase in serum corticosterone. These results suggest that combined defects of the conversion from inactive renin to active renin and aldosterone biosynthesis are the causes of selective hypoaldosteronism in our patient.

  13. Glutamate antagonists limit tumor growth

    OpenAIRE

    2001-01-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N...

  14. Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: possible involvement of bone morphogenetic protein-6 actions.

    Science.gov (United States)

    Otani, Hiroyuki; Otsuka, Fumio; Inagaki, Kenichi; Suzuki, Jiro; Miyoshi, Tomoko; Kano, Yoshihiro; Goto, Junko; Ogura, Toshio; Makino, Hirofumi

    2008-06-01

    Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, which is expressed in adrenocortical cells, enhances Ang II- but not potassium-induced aldosterone production in human adrenocortical cells. Accordingly, we examined the roles of BMP-6 in aldosterone breakthrough induced by long-term treatment with ARB. Ang II stimulated aldosterone production by adrenocortical cells. This Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis and CYP11B2 expression were attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartan-pretreated cells. Levels of Ang II type 1 receptor mRNA were not changed by chronic candesartan treatment. However, BMP-6 enhancement of Ang II-induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation, and BRE-Luc activity was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors activin receptor-like kinase-2 and activin type II receptor mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved

  15. The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

    Science.gov (United States)

    Wu, Vin-Cent; Wang, Shuo-Meng; Chueh, Shih-Chieh Jeff; Yang, Shao-Yu; Huang, Kuo-How; Lin, Yen-Hung; Wang, Jian-Jhong; Connolly, Rory; Hu, Ya-Hui; Gomez-Sanchez, Celso E.; Peng, Kang-Yung; Wu, Kwan-Dun

    2017-01-01

    Constitutive activation of the Wnt pathway/β-catenin signaling may be important in aldosterone-producing adenoma (APA). However, significant gaps remain in our understanding of the prevalence and clinical outcomes after adrenalectomy in APA patients harboring CTNNB1 mutations. The molecular expression of CYP11B2 and gonadal receptors in adenomas were also explored. Adenomas from 219 APA patients (95 men; 44.2%; aged 50.5 ± 11.9 years) showed a high rate of somatic mutations (n = 128, 58.4%). The majority of them harbored KCNJ5 mutations (n = 116, 52.9%); 8 patients (3.7%, 6 women) had CTNNB1 mutations. Patients with APAs harboring CTNNB1 mutations were older and had shorter duration of hypertension. After adrenalectomy, CTNNB1 mutation carriers had a higher possibility (87.5%) of residual hypertension than other APA patients. APAs harboring CTNNB1 mutations have heterogeneous staining of β-catenin and variable expression of gonadal receptors and both CYP11B1 and CYP11B2. This suggests that CTNNB1 mutations may be more related to tumorigenesis rather than excessive aldosterone production. PMID:28102204

  16. Renal function, aldosterone, and vasopressin excretion following repeated long-distance running.

    Science.gov (United States)

    Wade, C E; Dressendorfer, R H; O'Brien, J C; Claybaugh, J R

    1981-04-01

    Renal and endocrine responses were studied in 10 male runners during a 20-day 500-km race. Overnight urine and prerun blood samples were taken prior to running on days 1, 2, 5, 8, 14, 17, and 20. Day 13 followed 70 h of rest. Urine flow rate, osmotic clearance, tubular free water reabsorption, urinary vasopressin excretion rate, and body weight were not significantly changed. Creatinine clearance was constant except for an elevation on day 5. Plasma osmolality was elevated on days 2, 14, and 17. Plasma sodium was increased (P less than 0.05) on days 2 and 13 but reduced on day 20. The percentage of filtered sodium excreted was significantly reduced on all nights following running and elevated on recovery day 13. Urinary aldosterone excretion rate was significantly elevated 162, 117, and 97% on days 5, 8, and 20 and returned to control levels on day 13 after 70 h of rest. These data suggest that in response to repeated long-distance running normal fluid balance is regained within 12 h. However, it is necessary to conserve sodium for at least 24 h after exercise as evidenced by the decrease in the percent filtered sodium excreted and continued elevation of aldosterone excretion.

  17. A Rare Presentation of Primary Hyperparathyroidism with Concurrent Aldosterone-Producing Adrenal Carcinoma

    Directory of Open Access Journals (Sweden)

    Mario Molina-Ayala

    2015-01-01

    Full Text Available Aldosterone-producing adrenocortical carcinomas are an extremely rare cause of hyperaldosteronism (<1%. Coexistence of different endocrine tumors warrants additional screening for multiple endocrine neoplasia syndromes, especially in young patients with large or malignant masses. We present the case of a 40-year-old man with a history of hypertension that presented with an incidental left adrenal tumor during an ultrasound performed for nephrolithiasis. Biochemical assessment showed a mildly elevated calcium (11.1 mg/dL, high parathyroid hormone, and a plasma aldosterone concentration/plasma renin activity ratio of 124.5 (normal < 30, compatible with primary hyperparathyroidism with a concomitant primary hyperaldosteronism. A Tc99m-MIBI scintigraphy showed an abnormally increased tracer uptake in the right superior parathyroid and abdominal computed tomography confirmed a left adrenal tumor of 20 cm. The patient underwent parathyroidectomy and adrenalectomy with final pathology reports of parathyroid hyperplasia and adrenal carcinoma with biochemical remission of both endocrinopathies. He was started on chemotherapy, but the patient developed a frontal cortex and an arm metastasis and finally died less than one year later.

  18. Non-genomic aldosterone action: from the cell membrane to human physiology.

    Science.gov (United States)

    Lösel, Ralf; Feuring, Martin; Wehling, Martin

    2002-12-01

    According to the traditional model, steroid hormones bind to intracellular receptors and subsequently modulate transcription and protein synthesis, thus triggering genomic events finally responsible for delayed effects. In addition, very rapid effects of steroids mainly affecting intracellular signaling have been widely recognized which are clearly incompatible with the genomic model. These rapid, non-genomic steroid actions are likely to be transmitted via specific membrane receptors. Evidences for non-genomic steroid effects and distinct receptors involved are now presented for all steroid groups including vitamin D(3) and thyroid hormones. Mechanisms of action are being studied with regard to signal perception and transduction involved, and for various steroids including aldosterone a patchy sketch of a membrane receptor/second messenger cascade shows up being not essentially dissimilar to cascades involved in catecholamine or peptide hormone action. Aside non-classical membrane receptors with a high affinity for aldosterone, these effects involve phospholipase C, phosphoinositide turnover, intracellular pH and calcium, protein kinase C and tyrosine kinases. Increasing evidence is being accumulated for rapid physiological responses in humans, e.g. at the level of circulatory or metabolic effects, rendering clinical significance to these rapid actions.

  19. Effect of oral labetalol on plasma catecholamines, renin and aldosterone in patients with severe arterial hypertension.

    Science.gov (United States)

    Kornerup, H J; Pedersen, E B; Christensen, N J; Pedersen, A; Pedersen, G

    1979-11-01

    Arterial blood pressure and plasma catecholamines, renin activity and aldosterone concentration in 12 patients with severe essential hypertension were studied before and after combined alpha- and beta-adrenergic receptor blockage induced by oral labetalol treatment for 2 months. Furosemide in a fixed dose was employed as a basic antihypertensive agent throughout the study. Blood pressure was adequately controlled in only 6 patients. Mean body weight increased by 1.8 kg and there was a rise in body weight which was inversely correlated with the fall in standing mean blood pressure. The mean plasma noradrenaline concentration decreased from 0.30 to 0.20 ng/ml, whereas plasma adrenaline did not change significantly. Plasma renin activity and aldosterone concentration varied greatly, but the mean values did not change significantly. Change in body weight was correlated inversely with changes in plasma noradrenaline and renin. The results suggest that labetalol, through its combined alpha- and beta-adrenergic receptor blocking action, induces a rise in body weight, probably due to sodium and fluid retention, which partly counterbalances the antihypertensive effect of labetalol, and partly modifies both renin and sympathetic nervous activity.

  20. A Rare Presentation of Primary Hyperparathyroidism with Concurrent Aldosterone-Producing Adrenal Carcinoma

    Science.gov (United States)

    Molina-Ayala, Mario; Ramírez-Rentería, Claudia; Manguilar-León, Analleli; Paúl-Gaytán, Pedro; Ferreira-Hermosillo, Aldo

    2015-01-01

    Aldosterone-producing adrenocortical carcinomas are an extremely rare cause of hyperaldosteronism (<1%). Coexistence of different endocrine tumors warrants additional screening for multiple endocrine neoplasia syndromes, especially in young patients with large or malignant masses. We present the case of a 40-year-old man with a history of hypertension that presented with an incidental left adrenal tumor during an ultrasound performed for nephrolithiasis. Biochemical assessment showed a mildly elevated calcium (11.1 mg/dL), high parathyroid hormone, and a plasma aldosterone concentration/plasma renin activity ratio of 124.5 (normal < 30), compatible with primary hyperparathyroidism with a concomitant primary hyperaldosteronism. A Tc99m-MIBI scintigraphy showed an abnormally increased tracer uptake in the right superior parathyroid and abdominal computed tomography confirmed a left adrenal tumor of 20 cm. The patient underwent parathyroidectomy and adrenalectomy with final pathology reports of parathyroid hyperplasia and adrenal carcinoma with biochemical remission of both endocrinopathies. He was started on chemotherapy, but the patient developed a frontal cortex and an arm metastasis and finally died less than one year later. PMID:26161274

  1. Analysis of the Clinical Features of Adrenal Aldosterone Tumor and Idiopathic Aldosterone in Patients with Primary Aldosterone%浅析原发性醛固酮增多症中肾上腺醛固酮瘤和特发性醛固酮增多症的临床特点

    Institute of Scientific and Technical Information of China (English)

    赵伟军

    2016-01-01

    Objective To study the clinical characteristics of adrenal aldosterone tumor and idiopathic aldosterone in patients with primary aldosterone. Methods 16 cases with aldosterone-producing adenoma from July to December 2015 were selected as observation group, and 12 cases with idiopathic aldosterone gain were selected as control group. Clinical characteristics of two groups were compared. Results Lack the main results of the study data: patients in the observation group and the patients in the control group, serum potassium, potassium in the urine and urinary aldosterone and plasma aldosterone levels respectively: (2.44±0.37)mmol/L, (51.25±28.93) mmol/L, (55.45±28.93)nmol/L, (1240.94±783.37) pmol/L and (2.96±0.42) mmol/L, (59.83±29.01)mmol/L, (40.24±2.107) nmol/L, (709.21±546.62) pmol/L. Adrenal aldosterone producing adenoma and idiopathic hyperaldosteronism increased compared. The serum aldosterone levels and urinary aldosterone levels were significantly higher, and serum potassium level is relatively lower, and the difference was statistically significant (P<0.05). Conclusion The biochemical abnormalities of adrenal aldosterone tumor is relatively speaking, its characteristics are more obvious, which can be widely used in clinical practice.%目的:研究分析原发性醛固酮增多症中肾上腺醛固酮瘤和特发性醛固酮增多症的临床特点。方法选取2015年7~12月我院内分泌科所收治的肾上腺醛固酮瘤患者16例作为本研究观察组研究对象,12例特发性醛固酮增多症患者作为对照组,对比分析两组患者的临床特点。结果观察组患者与对照组患者血钾、尿钾、尿醛固酮以及血醛固酮水平分别为:(2.44±0.37)mmol/L、(51.25±28.93)mmol/L、(55.45±28.93)nmol/L、(1240.94±783.37)pmol/L 与(2.96±0.42) mmol/L、(59.83±29.01)mmol/L、(40.24±21.07)nmol/L、(709.21±546.62)pmol/L。肾上腺醛固酮瘤与特发性醛固酮增多症相比

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  3. Rapid screening test for primary hyperaldosteronism: ratio of plasma aldosterone to renin concentration determined by fully automated chemiluminescence immunoassays.

    NARCIS (Netherlands)

    Perschel, F.H.; Schemer, R.; Seiler, L.; Reincke, M.; Deinum, J.; Maser-Gluth, C.; Mechelhoff, D.; Tauber, R.; Diederich, S.

    2004-01-01

    BACKGROUND: The ratio of plasma aldosterone concentration to plasma renin activity (PAC/PRA) is the most common screening test for primary hyperaldosteronism (PHA), but it is not standardized among laboratories. We evaluated new automated assays for the simultaneous measurement of PAC and plasma ren

  4. Low plasma aldosterone despite normal plasma renin activity in uncomplicated type 1 diabetes mellitus : effects of RAAS stimulation

    NARCIS (Netherlands)

    Luik, PT; Kerstens, MN; Hoogenberg, K; Navis, GJ; Dullaart, RPF

    2003-01-01

    Background Data on levels and responsiveness of PRA and aldosterone in type 1 diabetes mellitus are conflicting. Earlier studies were not standardized with respect to the type of diabetes mellitus, the presence of diabetic complications or sodium intake. Therefore, we studied plasma renin activity a

  5. Discovery of Potential Inhibitors of Aldosterone Synthase from Chinese Herbs Using Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Simulation Studies

    Science.gov (United States)

    Lu, Fang; Qiao, Liansheng; Chen, Xi; Li, Gongyu

    2016-01-01

    Aldosterone synthase (CYP11B2) is a key enzyme for the biosynthesis of aldosterone, which plays a significant role for the regulation of blood pressure. Excess aldosterone can cause the dysregulation of the renin-angiotensin-aldosterone system (RAAS) and lead to hypertension. Therefore, research and development of CYP11B2 inhibitor are regarded as a novel approach for the treatment of hypertension. In this study, the pharmacophore models of CYP11B2 inhibitors were generated and the optimal model was used to identify potential CYP11B2 inhibitors from the Traditional Chinese Medicine Database (TCMD, Version 2009). The hits were further refined by molecular docking and the interactions between compounds and CYP11B2 were analyzed. Compounds with high Fitvalue, high docking score, and expected interactions with key residues were selected as potential CYP11B2 inhibitors. Two most promising compounds, ethyl caffeate and labiatenic acid, with high Fitvalue and docking score were reserved for molecular dynamics (MD) study. All of them have stability of ligand binding which suggested that they might perform the inhibitory effect on CYP11B2. This study provided candidates for novel drug-like CYP11B2 inhibitors by molecular simulation methods for the hypertension treatment. PMID:27781210

  6. Discovery of Potential Inhibitors of Aldosterone Synthase from Chinese Herbs Using Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Simulation Studies

    Directory of Open Access Journals (Sweden)

    Ganggang Luo

    2016-01-01

    Full Text Available Aldosterone synthase (CYP11B2 is a key enzyme for the biosynthesis of aldosterone, which plays a significant role for the regulation of blood pressure. Excess aldosterone can cause the dysregulation of the renin-angiotensin-aldosterone system (RAAS and lead to hypertension. Therefore, research and development of CYP11B2 inhibitor are regarded as a novel approach for the treatment of hypertension. In this study, the pharmacophore models of CYP11B2 inhibitors were generated and the optimal model was used to identify potential CYP11B2 inhibitors from the Traditional Chinese Medicine Database (TCMD, Version 2009. The hits were further refined by molecular docking and the interactions between compounds and CYP11B2 were analyzed. Compounds with high Fitvalue, high docking score, and expected interactions with key residues were selected as potential CYP11B2 inhibitors. Two most promising compounds, ethyl caffeate and labiatenic acid, with high Fitvalue and docking score were reserved for molecular dynamics (MD study. All of them have stability of ligand binding which suggested that they might perform the inhibitory effect on CYP11B2. This study provided candidates for novel drug-like CYP11B2 inhibitors by molecular simulation methods for the hypertension treatment.

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

    NARCIS (Netherlands)

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

    2008-01-01

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

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

    DEFF Research Database (Denmark)

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

    2006-01-01

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

  9. Preeclampsia -- a state of prostaglandin deficiency? Urinary prostaglandin excretion, the renin-aldosterone system, and circulating catecholamines in preeclampsia.

    Science.gov (United States)

    Pedersen, E B; Christensen, N J; Christensen, P; Johannesen, P; Kornerup, H J; Kristensen, S; Lauritsen, J G; Leyssac, P P; Rasmussen, A; Wohlert, M

    1983-01-01

    Urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), plasma concentrations of renin, aldosterone, norepinephrine (NE) and epinephrine (E) were determined during pregnancy, 5 days, 3, and 6 months after delivery in preeclampsia, normotensive pregnant, and nonpregnant control subjects. The PGE2 was higher in normotensive pregnant control subjects than in nonpregnant subjects. In preeclampsia, PGE2 was reduced to nonpregnant level. PGF2 alpha was the same in preeclampsia and in normotensive pregnancy, but elevated when compared to the normotensive nonpregnant control group. Plasma concentrations of renin and aldosterone were increased during pregnancy, but considerably less in preeclampsia than during normotensive pregnancy. NE and E were the same as in nonpregnant subjects during both hypertensive and normotensive pregnancy. All parameters were normal 3 months after delivery. There were no correlations between PGE2, PGF2 alpha, plasma concentrations of renin, aldosterone, NE, or E and blood pressure level in third trimester either in preeclampsia or in normotensive pregnancy. PGE2 was positively correlated to plasma concentrations of renin. It is suggested that the lack of renal PGE2 in preeclampsia might be responsible for the decrease in renal blood flow and sodium excretion. It is hypothesized that preeclampsia is a state of prostaglandin deficiency. The changes in the renin-aldosterone system may be secondary to changes in prostaglandin concentration both in preeclampsia and normotensive pregnancy.

  10. Plasma 18-hydroxycorticosterone and aldosterone responses to angiotensin II and corticotropin in diabetic patients with hyporeninemic and normoreninemic hypoaldosteronism.

    Science.gov (United States)

    Iwasaki, R; Kigoshi, T; Uchida, K; Morimoto, S

    1989-07-01

    To examine the nature of adrenal abnormalities in diabetic patients with hyporeninemic and normoreninemic hypoaldosteronism, responses of plasma 18-hydroxycorticosterone and plasma aldosterone to angiotension II infusions and ACTH injection were investigated in 8 diabetic patients with hyporeninemic hypoaldosteronism and 9 diabetic patients with normoreninemic hypoaldosteronism compared to 11 control subjects. In both the patients with hyporeninemic and normoreninemic hypoaldosteronism, plasma 18-hydroxycorticosterone and plasma aldosterone were low, whereas plasma cortisol and plasma corticosterone were within normal ranges. Percent increments of plasma 18-hydroxycorticosterone and plasma aldosterone above their baseline levels after angiotensin II infusions were low or somewhat low in the patients with hyporeninemic hypoaldosteronism and low in the patients with normoreninemic hypoaldosteronism. Percent increments of plasma 18-hydroxycorticosterone and plasma aldosterone above their baseline levels after ACTH injection were similar in three groups. These results suggest that in diabetic patients with isolated hypoaldosteronism, the adrenal abnormality, regardless of whether it is primary or secondary, is mainly due to impaired adrenal responsiveness to angiotension II and atrophy and the zona glomerulosa.

  11. Muscarinic Receptor Agonists and Antagonists

    Directory of Open Access Journals (Sweden)

    David R. Kelly

    2001-02-01

    Full Text Available A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes. Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

  12. Similar to spironolactone, oxymatrine is protective in aldosterone-induced cardiomyocyte injury via inhibition of calpain and apoptosis-inducing factor signaling.

    Directory of Open Access Journals (Sweden)

    Ting-Ting Xiao

    Full Text Available Accumulating evidence indicates that oxymatrine (OMT possesses variously pharmacological properties, especially on the cardiovascular system. We previously demonstrated that activated calpain/apoptosis-inducing factor (AIF-mediated pathway was the key molecular mechanism in aldosterone (ALD induces cardiomyocytes apoptosis. In the present study, we extended the experimentation by investigating the effect of OMT on cardiomyocytes exposed to ALD, as compared to spironolactone (Spiro, a classical ALD receptor antagonist. Cardiomyocytes were pre-incubated with OMT, Spiro or vehicle for 1 h, and then, cardiomyocytes were exposed to ALD 24 h. The cell injury was evaluated by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay and lactate dehydrogenase (LDH leakage ratio. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL assay, annexin V/PI staining, and relative caspase-3 activity assay. Furthermore, expression of pro-apoptotic proteins including truncated Bid (tBid, calpain and AIF were evaluated by western blot analysis. ALD stimulation increased cardiomyocytes apoptosis, caspase-3 activity and protein expression of calpain, tBid and AIF in the cytosol (p<0.05. Pre-incubated with cardiomyocytes injury and increased caspase-3 activity were significantly attenuated (p<0.05. Furthermore, OMT suppressed ALD-induced high expression of calpain and AIF. And these effects of OMT could be comparable to Spiro. These findings indicated that OMT might be a potential cardioprotective-agent against excessive ALD-induced cardiotoxicity, at least in part, mediated through inhibition of calpain/AIF signaling.

  13. Upregulation of Steroidogenic Acute Regulatory Protein by Hypoxia Stimulates Aldosterone Synthesis in Pulmonary Artery Endothelial Cells to Promote Pulmonary Vascular Fibrosis

    Science.gov (United States)

    Maron, Bradley A.; Oldham, William M.; Chan, Stephen Y.; Vargas, Sara O.; Arons, Elena; Zhang, Ying-Yi; Loscalzo, Joseph; Leopold, Jane A.

    2014-01-01

    Background The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension (PAH), suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in PAH. Methods and Results Patients with PAH, rats with Sugen/hypoxia-PAH, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia-StAR signaling in HPAECs. Hypoxia (2.0% FiO2) increased aldosterone levels selectively in HPAECs, which was confirmed by liquid chromatography-mass spectrometry. Increased aldosterone by hypoxia resulted from enhanced c-Fos/c-Jun binding to the proximal activator protein (AP-1) site of the StAR promoter in HPAECs, which increased StAR expression and activity. In HPAECs transfected with StAR-siRNA or treated with the AP-1 inhibitor, SR-11302, hypoxia failed to increase aldosterone, confirming that aldosterone biosynthesis required StAR activation by c-Fos/c-Jun. The functional consequences of aldosterone were confirmed by pharmacological inhibition of the mineralocorticoid receptor with spironolactone or eplerenone, which attenuated hypoxia-induced upregulation of the fibrogenic protein connective tissue growth factor and collagen III in vitro, and decreased pulmonary vascular fibrosis to improve pulmonary hypertension in Conclusions Our findings identify autonomous aldosterone synthesis in HPAECs due to hypoxia-mediated upregulation of StAR as a novel molecular mechanism that promotes pulmonary vascular

  14. 原发性醛固酮增多症的发病机制%Pathogenesis of primary aldosteronism

    Institute of Scientific and Technical Information of China (English)

    徐媛媛; 王卫庆

    2011-01-01

    Primary aldosteronism is one of the most common causes of secondary hypertension. Compared with essential hypertension patients who have same risk factors, impared cardiovascular, cerebrovascular and kidney damage are more prevalent in patients with primary aldosteronism. In recent years,with the further research of primary aldosteronism, it was shown that the pathogenesis of primary aldosteronism related to CYP11β2 gene polymorphisms, production of hybird gene, expression of ectopic adrenal receptors, 7p21-22gene and so on. Researches of pathogenesis of primary aldosteronism may provide a novel therapeutic strategy.%原发性醛固酮增多症是继发性高血压最常见的原因之一,与具有相同危险程度的原发性高血压患者比较,原发性醛固酮增多症患者心、脑血管及肾脏等靶器官的损伤更为多见.近年来,随着对原发性醛固酮增多症的深入研究,发现其发病机制涉及融合基因的产生、醛固酮合成酶(CYP11β2)基因多态性的改变、肾上腺异位受体的表达及7p21-22基因的改变等.对原发性醛固酮增多症发病机制的研究可能为此病的治疗开辟新的方向.

  15. Prognostic value of semiquantification NP-59 SPECT/CT in primary aldosteronism patients after adrenalectomy

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Ching-Chu; Cheng, Mei-Fang; Tzen, Kai-Yuan; Yen, Ruoh-Fang [National Taiwan University Hospital and National Taiwan University College of Medicine, Department of Nuclear Medicine, Taipei (China); Wu, Vin-Cent; Wu, Kwan-Dun [National Taiwan University Hospital and National Taiwan University College of Medicine, Department of Internal Medicine, Taipei (China); Liu, Kao-Lang [National Taiwan University Hospital and National Taiwan University College of Medicine, Department of Medical Imaging, Taipei (China); Lin, Wei-Chou [National Taiwan University Hospital and National Taiwan University College of Medicine, Department of Pathology, Taipei (China); Collaboration: the TAIPAI Study Group

    2014-07-15

    Primary aldosteronism (PA), characterized by an excessive production of aldosterone, affects 5-13 % of patients with hypertension. Accurate strategies are needed for the timely diagnosis of PA to allow curability and prevention of excessive cardiovascular events and related damage. This study aimed to evaluate the usefulness of semiquantification of {sup 131}I-6β-iodomethyl-norcholesterol (NP-59) single photon emission computed tomography (SPECT)/CT in differentiating aldosterone-producing adenoma (APA) from idiopathic adrenal hyperplasia (IAH) and in predicting clinical outcomes after adrenalectomy. We retrospectively reviewed 49 PA patients who had undergone adrenalectomy after NP-59 SPECT/CT within 1 year. A conventional visual scale (VS) and two semiquantitative parameters generated from SPECT/CT, adrenal to liver ratio (ALR) and lesion to contralateral ratio of bilateral adrenal glands (CON), with cutoff values calculated by receiver-operating characteristic (ROC) analysis, were compared with pathology results and postsurgical outcomes to determine the accuracy. An ALR cutoff of 1.84 and a CON cutoff of 1.15 showed an ability to distinguish adenoma from hyperplasia similar to VS (p = 0.2592 and 0.1908, respectively). An ALR cutoff of 2.28 and a CON cutoff of 1.11 yielded the highest sensitivity and specificity to predict postsurgical outcomes, and an ALR of 2.28 had an ability superior to VS (p = 0.0215), while a CON of 1.11 did not (p = 0.1015). Patients with either ALR or CON greater than the cutoff had a high probability of positive postsurgical outcomes (n = 36/38), while patients with both ALR and CON less than the cutoff had a low probability of positive postsurgical outcomes (n = 2/11). Semiquantification of NP-59 scintigraphy has an ability similar to VS in differentiating APA from IAH, but an excellent ability to predict postsurgical outcomes of adrenalectomy. An ALR or CON greater than the cutoff strongly suggests benefits from adrenalectomy, and

  16. Cortisol-induced inhibition of ovine renin and aldosterone responses to hypotension

    Energy Technology Data Exchange (ETDEWEB)

    Wood, C.E.; Silbiger, J.

    1987-03-01

    Previous studies from this laboratory have demonstrated that in preterm fetal sheep increases in plasma cortisol (F) concentration equal in amplitude to fetal F stress responses suppress plasma renin activity (PRA). The purpose of this study was to investigate the possibility that this negative interaction exists in adult sheep. Cortisol was measured by radioimmunoassay. Five conscious ewes with chronically prepared carotid arterial loops were infused intravenously with F or vehicle for 5 h. One hour after the end of F or vehicle infusion, renin secretion was stimulated by hypotension produced by infusion of sodium nitroprusside. F infusion increased plasma F; during vehicle infusion plasma F did not change. F infusion decreased hematocrit from 29 +/- 2 to 26 +/- 1%. Basal PRA in vehicle- and F-infused groups were 0.4 +/- 0 and 0.2 +/- 0.1 ng angiotensin I-ml/sup -1/-h/sup -1/ and did not change. In vehicle-infused ewes, PRA increased from 0.4 +/- 0 to 4.6 +/- 0.4 and plasma aldosterone from 26.0 +/- 1.0 to 173.1 +/- 21.8 pg/ml, while in F-infused ewes, PRA increased from 0.2 +/- 1 to 3.3 +/- 0.4 ng angiotensin I-ml/sup -1/-h/sup -1/ and aldosterone from 25.0 +/- 0 to 48.2 +/- 23.2 pg/ml, significantly smaller responses. These results suggest that repeated stress may modulate the responses of the renin-angiotensin system in this species.

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

    Science.gov (United States)

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

    2015-03-30

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

  18. Renal type a intercalated cells contain albumin in organelles with aldosterone-regulated abundance.

    Directory of Open Access Journals (Sweden)

    Thomas Buus Jensen

    Full Text Available Albumin has been identified in preparations of renal distal tubules and collecting ducts by mass spectrometry. This study aimed to establish whether albumin was a contaminant in those studies or actually present in the tubular cells, and if so, identify the albumin containing cells and commence exploration of the origin of the intracellular albumin. In addition to the expected proximal tubular albumin immunoreactivity, albumin was localized to mouse renal type-A intercalated cells and cells in the interstitium by three anti-albumin antibodies. Albumin did not colocalize with markers for early endosomes (EEA1, late endosomes/lysosomes (cathepsin D or recycling endosomes (Rab11. Immuno-gold electron microscopy confirmed the presence of albumin-containing large spherical membrane associated bodies in the basal parts of intercalated cells. Message for albumin was detected in mouse renal cortex as well as in a wide variety of other tissues by RT-PCR, but was absent from isolated connecting tubules and cortical collecting ducts. Wild type I MDCK cells showed robust uptake of fluorescein-albumin from the basolateral side but not from the apical side when grown on permeable support. Only a subset of cells with low peanut agglutinin binding took up albumin. Albumin-aldosterone conjugates were also internalized from the basolateral side by MDCK cells. Aldosterone administration for 24 and 48 hours decreased albumin abundance in connecting tubules and cortical collecting ducts from mouse kidneys. We suggest that albumin is produced within the renal interstitium and taken up from the basolateral side by type-A intercalated cells by clathrin and dynamin independent pathways and speculate that the protein might act as a carrier of less water-soluble substances across the renal interstitium from the capillaries to the tubular cells.

  19. Gene Expression Profile of Persistent Postoperative Hypertension Patients with Aldosterone-producing Adenomas

    Institute of Scientific and Technical Information of China (English)

    Li-Fang Xie; Jin-Zhi Ouyang; An-Ping Wang; Wen-Bo Wang; Xin-Tao Li; Bao-Jun Wang; Yi-Ming Mu

    2015-01-01

    Background:Hypertension often persists after adrenalectomy for primary aldosteronism (PA).Many studies have analyzed the outcomes of adrenalectomy for aldosterone-producing adenomas (APA) to identify predictive factors for persistent hypertension.However,differentially expressed genes in persistent postoperative hypertension remain unknown.Our aim was to describe gene expression profile of persistent postoperative hypertension patients with APA.Methods:In this study,we described and compared gene expression profiles in persistent postoperative hypertension and postoperative normotension in Chinese patients with APA using microarray analysis.Confirmation was performed with quantitative real time-polymerase chain reaction analysis.Bioinformatic analysis (gene ontology analysis,pathway analysis and network analysis) was used for further research.Results:Microarray analysis identified a total of 99 differentially expressed genes,including 18 up-regulated and 81 down-regulated genes.Among the dysregulated genes were fat atypical cadherin 1 as well as fatty acid binding protein 4 and other genes that have not been previously studied in persistent postoperative hypertension with APA.Bioinformatics analysis indicated that differentially expressed genes were associated with lipid metabolic process,metal ion binding,and cell differentiation.Pathway analysis determined that five pathways corresponded to the dysregulated transcripts.The mRNAs-ncRNAs co-expression network was composed of 49 network nodes and 72 connections between 18 coding genes and 31 noncoding genes.Conclusions:This study revealed differentially expressed genes in persistent postoperative hypertension with APA and provided a resource of candidate genes for exploration of possible drug targets and prognostic markers.

  20. Responsiveness of the renin-aldosterone system during exercise in young patients with essential hypertension.

    Science.gov (United States)

    Pedersen, E B; Kornerup, H J; Larsen, J S

    1981-10-01

    The effect of exercise of gradually increased intensity, i.e. 75 W for 20 min followed by 100 W for 20 min, on plasma renin concentration (PRC) and plasma aldosterone concentration (PAC) was studied in young patients with essential hypertension and normotensive control subjects. During exercise without previous sodium loading PRC and PAC increased to the same degree in both hypertensives and normotensives during light exercise; PRC increased further significantly in the normotensives (63 to 72 microIU/ml (medians), P less than 0.01) but not in the hypertensives (46 to 51 microIU/ml) during heavy exercise. PRC and PAC were significantly correlated during both 75 W (rho = 0.633, P less than 0.05) and 100 W (rho = 0.635, P less than 0.05) exercise in the normotensives, but not in the hypertensives. During exercise after loading with 500 ml sodium chloride (0.85 mol/l) PRC and PAC increased in both hypertensives (28 to 42 microIU/ml, P less than 0.01; 0.11 to 0.53 nmol/l, P less than 0.01) and normotensives (22 to 33 microIU/ml, P less than 0.02; 0.12 to 0.34 nmol/l, P less than 0.01), although to a considerably lower degree than without previous loading. PRC and PAC were, however, significantly higher in the hypertensive than in the normotensive group after exercise. It is suggested that the responsiveness of the renin-aldosterone system is abnormal during exercise in young patients with mild essential hypertension, both without and with previous intravenous sodium loading.

  1. Role of extracellular signal-regulated kinases in aldosterone-induced rat mesangial cells proliferation%细胞外信号调节蛋白激酶介导醛固酮诱导的肾小球系膜细胞增殖

    Institute of Scientific and Technical Information of China (English)

    姚丽; 孙立; 魏敏; 葛丹梅; 王力宁

    2011-01-01

    ERK1/2 activation induced by aldosterone was at a concentration of 100 nmol/L. Aldosterone (100 nmol/L)-induced activation of ERK1/2 peaked at 10 minutes (P<0.05).Pretreatment with a selective MR antagonist eplerenone (1 μmol/L) significantly attenuated aldosterone-induced ERK1/2 phosphorylation. Aldosterone (100 nmol/L) treatment for 30 hours increased [3H]-thymidine incorporation of RMCs (135% ±8% of controls, P <0.05). Cellular proliferation induced by aldosterone could be prevented by pretreatment with eplerenone or an ERK (MEK) inhibitor PD988059. Conclusion Aldosterone induces RMCs proliferation through MR and ERK1/2 activation, which may contribute to the pathogenesis of glomerular mesangial injury.

  2. Effect of aldosterone on rat peritoneal fibrosis induced by peritoneal dia-lysis%醛固酮在腹膜透析大鼠腹膜纤维化中的作用

    Institute of Scientific and Technical Information of China (English)

    任连升; 郝建兵; 张蕾; 郝丽荣

    2015-01-01

    AIM:To investigate the pathologic role of aldosterone and protective effect of aldosterone receptor antagonist on peritoneal fibrosis in peritoneal dialysis rats .METHODS:A peritoneal fibrosis rat model was established by intraperitoneal injection of lipopolysaccharide ( at 1 d, 3 d, 5 d and 7 d, 0.6 mg/kg) and dialysate ( daily intraperitoneal injection of 4.25%dialysate, 100 mL/kg).At the same time, spironolactone (an aldosterone receptor antagonist , 100 mg・ kg -1・ d-1 ) was given to the model rats .After 4 weeks, the expression of aldosterone synthase CYP 11B2, 11β-hydrox-ysteroid dehydrogenase type 2 (11β-HSD2), mineralocorticoid receptor (MCR), and inflammatory factors were detected by immunohistochemistry , real-time PCR and Western blotting .RESULTS:The rat model of peritoneal fibrosis was suc-cessfully established .At the same time, the injury of mesothelial cells , deposition of collagen fibers and thickness of perito-neal were increased .Moreover , the infiltration of macrophages in the peritoneum/dialysate was increased .The level of al-dosterone and the expression of MCR , 11β-HSD2 and CYP11B2 in fibrotic peritoneum were obviously up-regulated as com-pared with normal rats .The expression of NF-κB/MCP-1 was also increased .However , treatment with spironolactone alle-viated peritoneal fibrosis and reduced the expression of NF-κB/MCP-1.CONCLUSION:Local aldosterone is involved in the process of peritoneal fibrosis via NF-κB/MCP-1 pathway.Spironolactone alleviates peritoneal fibrosis of peritoneal dial-ysis.%目的:研究醛固酮在腹膜透析大鼠腹膜纤维化中的作用,以及醛固酮受体拮抗剂是否能够减轻腹膜纤维化。方法:通过腹腔注射脂多糖(第1、3、5、7天,0.6 mg/kg)+透析液(每天腹腔注射4.25%含糖透析液100 mL/kg )建立伴有腹膜纤维化的腹膜透析大鼠模型。同时给予醛固酮受体拮抗剂(螺内酯,100 mg・ kg-1・d-1)灌胃。4周后取

  3. Somatotropin as the non-ACTH factor of anterior pituitary origin for the maintenance of enhanced aldosterone secretory responsiveness of dietary sodium restriction in chronically hypophysectomized rats

    NARCIS (Netherlands)

    Lee, T.C.; Wied, D. de

    1968-01-01

    Somatotropin treatment in chronically hypophysectomized, sodium-deprived rats effectively restored to treated animals the distinct and enhanced aldosterone secretory responsiveness of the adrenal which characterizes the adrenals of intact rats subjected to dietary sodium restriction, but absent in c

  4. New antagonist agents of neuropeptide y receptors

    Directory of Open Access Journals (Sweden)

    Ignacio Aldana

    2000-12-01

    Full Text Available In the CNS, NPY has been implicated in obesity and feeding, endocrine function and metabolism. Potent and selective rNPY antagonists will be able to probe the merits of this approach for the treatment of obesity. We report the synthesis and preliminary evaluation of some hydrazide derivatives as antagonists of rNPY.

  5. Effects of low-sodium diet vs. high-sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride (Cochrane Review)

    DEFF Research Database (Denmark)

    Graudal, Niels A; Hubeck-Graudal, Thorbjørn; Jürgens, Gesche

    2012-01-01

    The question of whether reduced sodium intake is effective as a health prophylaxis initiative is unsolved. The purpose was to estimate the effects of low-sodium vs. high-sodium intake on blood pressure (BP), renin, aldosterone, catecholamines, and lipids.......The question of whether reduced sodium intake is effective as a health prophylaxis initiative is unsolved. The purpose was to estimate the effects of low-sodium vs. high-sodium intake on blood pressure (BP), renin, aldosterone, catecholamines, and lipids....

  6. Changes in cardiac aldosterone and its synthase in rats with chronic heart failure: an intervention study of long-term treatment with recombinant human brain natriuretic peptide

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, X.Q. [Fujian Medical University Union Hospital, Fuzhou, Fujian (China); Department of Cardiology, The Central Hospital of Enshi Autonomous Prefecture, Enshi, Hubei (China); Hong, H.S. [Department of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, Fujian (China); Lin, X.H. [Department of Emergency Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian (China); Chen, L.L. [Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, Fujian (China); Li, Y.H. [Department of Cardiology, The Central Hospital of Enshi Autonomous Prefecture, Enshi, Hubei (China)

    2014-07-11

    The physiological mechanisms involved in isoproterenol (ISO)-induced chronic heart failure (CHF) are not fully understood. In this study, we investigated local changes in cardiac aldosterone and its synthase in rats with ISO-induced CHF, and evaluated the effects of treatment with recombinant human brain natriuretic peptide (rhBNP). Sprague-Dawley rats were divided into 4 different groups. Fifty rats received subcutaneous ISO injections to induce CHF and the control group (n=10) received equal volumes of saline. After establishing the rat model, 9 CHF rats received no further treatment, rats in the low-dose group (n=8) received 22.5 μg/kg rhBNP and those in the high-dose group (n=8) received 45 μg/kg rhBNP daily for 1 month. Cardiac function was assessed by echocardiographic and hemodynamic analysis. Collagen volume fraction (CVF) was determined. Plasma and myocardial aldosterone concentrations were determined using radioimmunoassay. Myocardial aldosterone synthase (CYP11B2) was detected by quantitative real-time PCR. Cardiac function was significantly lower in the CHF group than in the control group (P<0.01), whereas CVF, plasma and myocardial aldosterone, and CYP11B2 transcription were significantly higher than in the control group (P<0.05). Low and high doses of rhBNP significantly improved hemodynamics (P<0.01) and cardiac function (P<0.05) and reduced CVF, plasma and myocardial aldosterone, and CYP11B2 transcription (P<0.05). There were no significant differences between the rhBNP dose groups (P>0.05). Elevated cardiac aldosterone and upregulation of aldosterone synthase expression were detected in rats with ISO-induced CHF. Administration of rhBNP improved hemodynamics and ventricular remodeling and reduced myocardial fibrosis, possibly by downregulating CYP11B2 transcription and reducing myocardial aldosterone synthesis.

  7. Aldosterone Inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to Decrease Pulmonary Endothelial Nitric Oxide Levels and Modulate Pulmonary Arterial Hypertension

    Science.gov (United States)

    Maron, Bradley A.; Zhang, Ying-Yi; White, Kevin; Chan, Stephen Y.; Handy, Diane E.; Mahoney, Christopher E.; Loscalzo, Joseph; Leopold, Jane A.

    2012-01-01

    Background Pulmonary arterial hypertension (PAH) is characterized, in part, by decreased endothelial nitric oxide (NO•) production and elevated levels of endothelin-1. Endothelin-1 is known to stimulate endothelial nitric oxide synthase (eNOS) via the endothelin-B receptor (ETB), suggesting that this signaling pathway is perturbed in PAH. Endothelin-1 also stimulates adrenal aldosterone synthesis; in systemic blood vessels, hyperaldosteronism induces vascular dysfunction by increasing endothelial reactive oxygen species (ROS) generation and decreasing NO• levels. We hypothesized that aldosterone modulates PAH by disrupting ETB-eNOS signaling through a mechanism involving increased pulmonary endothelial oxidant stress. Methods and Results In rats with PAH, elevated endothelin-1 levels were associated with elevated aldosterone levels in plasma and lung tissue and decreased lung NO• metabolites in the absence of left heart failure. In human pulmonary artery endothelial cells (HPAECs), endothelin-1 increased aldosterone levels via PGC-1α/steroidogenesis factor-1-dependent upregulation of aldosterone synthase. Aldosterone also increased ROS production, which oxidatively modified cysteinyl thiols in the eNOS-activating region of ETB to decrease endothelin-1-stimulated eNOS activity. Substitution of ETB-Cys405 with alanine improved ETB-dependent NO• synthesis under conditions of oxidant stress, confirming that Cys405 is a redox sensitive thiol that is necessary for ETB-eNOS signaling. In HPAECs, mineralocorticoid receptor antagonism with spironolactone decreased aldosterone-mediated ROS generation and restored ETB-dependent NO• production. Spironolactone or eplerenone prevented or reversed pulmonary vascular remodeling and improved cardiopulmonary hemodynamics in two animal models of PAH in vivo. Conclusions Our findings demonstrate that aldosterone modulates an ETB cysteinyl thiol redox switch to decrease pulmonary endothelium-derived NO• and promote PAH

  8. Effect of heat stress and drinking water salt supplements on plasma electrolytes and aldosterone concentration in broiler chickens

    Science.gov (United States)

    Deyhim, F.; Teeter, R. G.

    1995-12-01

    An experiment was conducted to evaluate the effects of supplementing drinking water with isomolar (0.067 mol/l) KCl or NaCl on mass gain, food and water consumption, rectal temperature, and plasma concentrations of aldosterone, Na+, and K+ in broiler chickens reared in thermoneutral and cycling heat stressing environments. Heat stress decreased ( P≤0.05) mass gain, food consumption, and plasma concentrations of Na+ and K+, while increases ( P≤0.05) in plasma concentrations of aldosterone, rectal temperature, and water consumption were observed. Drinking water supplemented with either KCl or NaCl increased ( P≤0.05) broiler mass gain and water consumption, but had no effect ( P>0.1) on the other variables evaluated. The results of this study indicate that broiler chickens in a heat stress environment are under osmotic stress and supplementing drinking water with 0.067 mol/1 KCl or NaCl does not lessen this stress.

  9. The influence of certain molecular descriptors of fecal elimination of angiotensin II receptor antagonists

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    Trbojević-Stanković Jasna B.

    2015-01-01

    Full Text Available Angiotensin II receptor antagonists (ARBs modulate the function of the renin-angiotensin-aldosterone system and are commonly prescribed antihypertensive drugs, especially in patients with renal failure. In this study, the relationship between several molecular properties of seven ARBs (candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan and their fecal elimination data obtained from the literature were investigated. The ARB molecular descriptors were calculated using three software packages. Simple linear regression analysis showed the best 2 correlation between fecal elimination data and lipophilicity descriptor, ClogP values (R2 = 0.725. Multiple linear regression was applied to examine the correlation of ARBs’ fecal elimination data with their lipophilicity and one additional, calculated descriptor. The best correlation (R2 = 0.909 with an acceptable probability value, P <0.05 was established between the ARB fecal elimination data and their lipophilicity and aqueous solubility data. Applying computed molecular descriptors for evaluating drug elimination is of great importance in drug research.

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

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    Künzel Heike

    2003-10-01

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

  11. Plasma soluble (pro)renin receptor is independent of plasma renin, prorenin, and aldosterone concentrations but is affected by ethnicity.

    Science.gov (United States)

    Nguyen, Geneviève; Blanchard, Anne; Curis, Emmanuel; Bergerot, Damien; Chambon, Yann; Hirose, Takuo; Caumont-Prim, Aurore; Tabard, Sylvie Brailly; Baron, Stéphanie; Frank, Michael; Totsune, Kazuhito; Azizi, Michel

    2014-02-01

    A soluble (pro)renin receptor (sPRR) circulates in plasma and is able to bind renin and prorenin. It is not known whether plasma sPRR concentrations vary with the activity of the renin-angiotensin system. We measured plasma sPRR, renin, prorenin, and aldosterone concentrations in 121 white and 9 black healthy subjects, 40 patients with diabetes mellitus, 41 hypertensive patients with or without renin-angiotensin system blockers, 9 patients with primary aldosteronism, and 10 patients with Gitelman syndrome. Median physiological plasma sPRR concentration was 23.5 ng/mL (interquartile range, 20.9-26.5) under usual uncontrolled sodium diet. sPRR concentration in healthy subjects, unlike renin and prorenin, did not display circadian variation or dependence on age, sex, posture, or hormonal status. sPRR concentrations were ≈25% lower in black than in white subjects, whereas renin concentrations were ≈40% lower. Patients with diabetes mellitus (average renin-high prorenin levels) and with hypertension only (average renin-average prorenin levels) had sPRR concentrations similar to healthy subjects. Renin-angiotensin system blockade was associated with increase of sPRR concentration by ≈12%. sPRR in patients with primary aldosteronism (low renin-low prorenin) and Gitelman syndrome (high renin-high prorenin) were similar and ≈10% higher than in healthy subjects. There was no correlation between sPRR and renin or prorenin. In conclusion, our results show that plasma sPRR concentrations are dependent on ethnicity and independent of renin, prorenin, and aldosterone concentrations in healthy subjects and in patients with contrasted degrees of renin-angiotensin system activity.

  12. Aldosterone Response in Severe Hypokalemia and Volume Depletion: A Case Report and Review of the Recent Research

    Directory of Open Access Journals (Sweden)

    Keiko Kai

    2016-01-01

    Full Text Available We report a case of severe hypokalemia and volume depletion complicated by chronic watery diarrhea resulting from chronic alcoholism in a 57-year-old man. Prompt replacement of normal saline with potassium chloride and cessation of alcohol intake resulted in a favorable outcome. We discuss the pathophysiology of the case, emphasizing the response of aldosterone in both hypokalemia and volume depletion, and provide a review of recent research.

  13. Oxidative damages in tubular epithelial cells in IgA nephropathy: role of crosstalk between angiotensin II and aldosterone

    Directory of Open Access Journals (Sweden)

    Lim Ai-Ing

    2011-10-01

    Full Text Available Abstract Background Inhibition of the renin-angiotensin-aldosterone system (RAAS slows down the progression of chronic renal diseases (CKD including IgA nephropathy (IgAN. Herein, we studied the pathogenetic roles of aldosterone (Aldo in IgAN. Methods Human mesangial cells (HMC was activated with polymeric IgA (pIgA from IgAN patients and the effects on the expression of RAAS components and TGF-β synthesis examined. To study the roles of RAAS in the glomerulotubular communication, proximal tubular epithelial cells (PTEC was cultured with conditioned medium from pIgA-activated HMC with eplerenone or PD123319, the associated apoptotic event was measured by the generation of nicotinamide adenine dinucleotide phosphate (NADPH oxidase and reactive oxygen species (ROS. Results Polymeric IgA up-regulated the Aldo synthesis and aldosterone synthase expression by HMC. The release of TGF-β by HMC was up-regulated synergistically by AngII and Aldo and this was inhibited by incubation of HMC with losartan plus eplerenone. Cultured PTEC express the mineralocorticoid receptor, but not synthesizing aldosterone. Apoptosis, demonstrated by cleaved PARP expression and caspase 3 activity, was induced in PTEC activated by conditioned medium prepared from HMC cultured with pIgA from IgAN patients. This apoptotic event was associated with increased generation of NADPH oxidase and ROS. Pre-incubation of PTEC with PD123319 and eplerenone achieved complete inhibition of PTEC apoptosis. Conclusions Our data suggest that AngII and Aldo, released by pIgA activated HMC, served as mediators for inducing apoptosis of PTEC in glomerulo-tubular communications. Crosstalk between AngII and Aldo could participate in determining the tubular pathology of IgAN.

  14. Correlation between Serum Aldosterone Level and Hearing Condition of Elderly Patients Referred to Otolaryngology Services of Hamadan, Western Iran

    Directory of Open Access Journals (Sweden)

    Dr. Farhad Farahani

    2010-06-01

    Full Text Available Background and Aim: Recently, more attention was paid to the direct protective effect of aldosterone against hearing impairment in elderly patients. The aim of this study was determination of possible correlation between serum aldosterone level and hearing condition of elderly patients that referred to the Otolaryngology services of Hamadan in 2005-2006.Methods: In this case control study 54 (27 males,27 females persons above 60 years old were evaluated. They contained twenty eight cases with normal hearing and 26 cases with presbycusis. Persons with any abnormal biochemical finding or history of conditions that predispose them to the sensorineural hearing loss (SNHL were excluded. In both groups serum level of sodium, potassium and aldosterone were measured and hearing condition evaluated by puretone, speech and immitance audiometry.Results: Statistical relationship between serum aldostrone level and hearing condition, sex, configuration of audiogram and speech discrimination score (SDS were not significant. In addition, no significant relationship between sodium and potassium levels with hearing condition was found (p>0.05.Conclusion: This study could not confirm protective effect of aldostrone against presbycusis. This discrepancy may originate from epidemiologic differences, laboratory errors or small sample size.

  15. Eplerenone-Mediated Aldosterone Blockade Prevents Renal Fibrosis by Reducing Renal Inflammation, Interstitial Cell Proliferation and Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Hui Chen

    2013-11-01

    Full Text Available Background/Aims: Prolonged elevation of serum aldosterone leads to renal fibrosis. Inflammation also plays a role in the pathogenesis of renal disease. We used a rat model of interstitial renal fibrosis to test the hypothesis that eplerenone-mediated aldosterone blockade prevents renal fibrosis due to its anti-inflammatory and anti-proliferative effects. Methods: Eplerenone (a selective aldosterone blocker or vehicle (control, was given to male Wistar rats (50 mg/kg, twice daily for 7 days before unilateral ureteral obstruction (UUO and for an additional 28 days after surgery. Body weight, blood pressure, renal histo-morphology, immune-staining for macrophages, monocyte chemotactic protein-1, proliferating cell nuclear antigen, α-smooth muscle actin, and serum and urine markers of renal function and oxidative stress were determined for both groups on 7, 14, and 28 days after surgery. Results: Epleronone had no effect on body weight or blood pressure. However, eplerenone inhibited the development of renal fibrosis, inflammation (macrophage and monocyte infiltration, interstitial cell proliferation, and activation of interstitial cells (α-SMA expression. Epleronone also reduced oxidative stress. Conclusion: The anti-fibrotic effect of eplerenone appears to be unrelated to its effect on blood pressure. Eplerenone inhibits renal inflammation, interstitial cell proliferation, phenotypic changes of interstitial cells, and reduces oxidative stress.

  16. Catheterization during adrenal vein sampling for primary aldosteronism: failure to use (1-24) ACTH may increase apparent failure rate.

    Science.gov (United States)

    Kline, Gregory A; So, Benny; Dias, Valerian C; Harvey, Adrian; Pasieka, Janice L

    2013-07-01

    "Successful" adrenal vein catheterization in primary aldosteronism (PA) is often defined by a ratio of >3:1 of cortisol in the adrenal vein vs the inferior vena cava. Non-use of corticotropin (ACTH) during sampling may increase the apparent failure rate of adrenal vein catheterization due to lower cortisol levels. A retrospective study was performed on all patients with confirmed unilateral PA between June 2005 and August 2011. Adrenal vein sampling (AVS) included simultaneous bilateral baseline samples with repeat sampling 15 minutes after intravenous infusion of 250 μg of Cortrosyn (ACTH-S). Successful catheter placement was judged as adrenal cortisol:IVC cortisol of >3:1, applied to both baseline and ACTH-S samples and lateralization of aldosteronism was judged as normalized aldosterone/cortisol (A/C) ratio >3 times the contralateral A/C ratio. In ACTH-S samples, 94% of right-sided catheterizations were biochemically successful with 100% success on the left. Among baseline samples, only 47% of right- and 44% of left-sided samples met the 3:1 cortisol criteria. However, 95% of apparent "failed" baseline cortisol sets still showed lateralization of A/C ratios that matched the ultimate pathology. Non-ACTH-stimulated samples may be incorrectly judged as failed catheter placement when a 3:1 ratio is used. ACTH-stimulated sampling is the preferred means to confirm catheterization during AVS.

  17. Effect of progesterone on renal sodium handling in man: relation to aldosterone excretion and plasma renin activity.

    Science.gov (United States)

    Oparil, S; Ehrlich, E N; Lindheimer, M D

    1975-08-01

    1. The effect of progesterone on renal haemodynamics and intrarenal sodium handing was evaluated in thirteen normal men on a constant diet. Clearances were measured during maximal water diuresis and again 4-7 days later, this time 3 h after progesterone was given intramuscularly. Seven additional studies were performed 3 days after progesterone administration. Another four tests were performed on volunteers who had manifested renal 'escape' from the sodium-retaining effect of deoxycorticosterone acetate. 2. In acute progesterone studies glomerular filtration rate was unchanged, whereas effective renal plasma flow increased, so that filtration fraction decreased significantly. A similar in crease in urinary sodium occurred whether subjects received a low or high sodium diet. Indices which related to the distal delivery of filtrate (fractional urine flow and the sum of fractional free water and sodium clearances) increased significantly in both groups. The progesterone-induced increase in sodium excretion was not related to changes in plasma renin activity, renin substrate or urinary aldosterone. After 3 days of progesterone, the increase of sodium excretion was less than in the acute studies and urinary aldosterone increased tow- to four-fold. Progesterone failed to produce an acute increse in urinary sodium in subjects hyperexpanded by administration of exogenous mineralocorticoids. 3. Results suggest that the acute natriuretic action of progesterone is in part independent of aldosterone inhibition and that progesterone may inhibit sodium reabsorption at proximal as well as distal sites in the nephron.

  18. Antagonists of the kappa opioid receptor.

    Science.gov (United States)

    Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, Edward

    2014-05-01

    The research community has increasingly focused on the development of OPRK antagonists as pharmacotherapies for the treatment of depression, anxiety, addictive disorders and other psychiatric conditions produced or exacerbated by stress. Short-acting OPRK antagonists have been recently developed as a potential improvement over long-acting prototypic ligands including nor-BNI and JDTic. Remarkably the short-acting LY2456302 is undergoing phase II clinical trials for the augmentation of the antidepressant therapy in treatment-resistant depression. This Letter reviews relevant chemical and pharmacological advances in the identification and development of OPRK antagonists.

  19. Antagonistic formation motion of cooperative agents

    Institute of Scientific and Technical Information of China (English)

    卢婉婷; 代明香; 薛方正

    2015-01-01

    This paper investigates a new formation motion problem of a class of first-order multi-agent systems with antagonis-tic interactions. A distributed formation control algorithm is proposed for each agent to realize the antagonistic formation motion. A sufficient condition is derived to ensure that all agents make an antagonistic formation motion in a distributed manner. It is shown that all agents can be spontaneously divided into several groups, and agents in the same group collab-orate while agents in different groups compete. Finally, a numerical simulation is included to demonstrate our theoretical results.

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

    Directory of Open Access Journals (Sweden)

    Karl Andersen

    2009-03-01

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

  1. Effect of hemorrhage on cardiac output, vasopressin, aldosterone, and diuresis during immersion in men

    Science.gov (United States)

    Greenleaf, J. E.; Simanonok, K.; Bernauer, E. M.; Wade, C. E.; Keil, L. C.

    1992-01-01

    The purpose of this research was to test the hypotesis that a reduction in blood volume would attenuate or eliminate immersion-induced increases in cardiac output (Q(sub co)) and urine excretion, and to investigate accompanying vasoactive and fluid-electrolyte hormonal responses. Eight men (19-23 yr) were supine during a 2-hr control period in air, and then sat for 5-hr test periods in air at 20 C (dry control, DC); water at 34.5 C (wet control, WC); and water (34.5 C) after hemorrhage (WH) of 14.8 plus or minus 0.3 percent of their blood volume. Blood volume was -11.6 plus or minus 0.6 percent at immersion (time 0). Mean (bar-X hrs 1-5) Q(sub co) was unchanged in WC (5.3 plus or minus 0.01 l/min) and in WH (4.5 plus or minus 0.1 l/min), but decreased (P less than 0.05) in DC to 3.6 plus or minus 0.1 l/min. Mean urine excretion rates were 1.0 plus or minus 0.2 ml/min for DC and 1.1 plus or minus 0.2 ml/min for WH; both were lower (P less than 0.05) than that for WC of 2.0 plus or minus 0.4 ml/min. Plasma (Na+) and (Osm) were unchanged in all experiments. Mean plasma vasopressin (PVP) (bar-X hrs 1-5) was 1.1 plus or minus 0.1 pg/ml in WC, and higher (P less than 0.05) in DC (2.1 plus or minus 0.2 pg/ml)and WH (2.1 plus or minus 0.1 pg/ml); it was unchanged during air and water test periods. Thus, hemorrhage attenuated the immersion-induced increase in Q(sub co), eliminated the WC diuresis, maintained plasma renin activity and PVP at DC levels and did not change immersion-induced aldosterone suppression; the osmotic diuresis during control immersion is apparently not due to either aldosterone suppression or vasopressin suppression.

  2. Benzodiazepine receptor antagonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy....

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

    Directory of Open Access Journals (Sweden)

    Agata Kujawa-Szewieczek

    2010-08-01

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

  4. Effect of hydration on plasma vasopressin, renin, and aldosterone responses to head-up tilt

    Science.gov (United States)

    Harrison, M. H.; Geelen, G.; Keil, L. C.; Wade, C. A.; Hill, L. C.

    1986-01-01

    If plasma vasopressin (PVP), plasma renin (PRA), and plasma aldosterone (PA) responses to change in posture are mediated only by alterations in intrathoracic baroreceptor activity hydration status should have minimal influence on these responses. To test this hypothesis, six male subjects underwent 45 min of 70 deg head-up tilt (HUT) following 26 h dehydration, and again, 105 min later, following rehydration. Compared with preceding supine hydrated control values, PVP, PRA, and PA increased (p less than 0.001) during dehydrated HUT, but only PVP and PRA increased during rehydrated HUT (p less than 0.001). The dissociation during rehydrated HUT of PRA and PA may have been related more to the reduction (p less than 0.001) in plasma potassium concentration than to the accompanying decrease (p less than 0.001) in plasma osmolality and sodium concentration. Although increases in PVP and PRA during HUT were attenuated (p less than 0.01) following rehydration, this attenuation was associated with the absence of symptoms of overt hypotension following rehydration. However, since rehydration did not abolish the increases in PVP and PRA induced by HUT, it is concluded that the present observations support the concept of intrathoracic baroreceptor involvement in the regulation of vasopressin secretion and renin release.

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

    Science.gov (United States)

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

    2015-05-20

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

  6. Direct control of Na(+)-K(+)-2Cl(-)-cotransport protein (NKCC1) expression with aldosterone.

    Science.gov (United States)

    Ding, Bo; Frisina, Robert D; Zhu, Xiaoxia; Sakai, Yoshihisa; Sokolowski, Bernd; Walton, Joseph P

    2014-01-01

    Sodium/potassium/chloride cotransporter (NKCC1) proteins play important roles in Na(+) and K(+) concentrations in key physiological systems, including cardiac, vascular, renal, nervous, and sensory systems. NKCC1 levels and functionality are altered in certain disease states, and tend to decline with age. A sensitive, effective way of regulating NKCC1 protein expression has significant biotherapeutic possibilities. The purpose of the present investigation was to determine if the naturally occurring hormone aldosterone (ALD) could regulate NKCC1 protein expression. Application of ALD to a human cell line (HT-29) revealed that ALD can regulate NKCC1 protein expression, quite sensitively and rapidly, independent of mRNA expression changes. Utilization of a specific inhibitor of mineralocorticoid receptors, eplerenone, implicated these receptors as part of the ALD mechanism of action. Further experiments with cycloheximide (protein synthesis inhibitor) and MG132 (proteasome inhibitor) revealed that ALD can upregulate NKCC1 by increasing protein stability, i.e., reducing ubiquitination of NKCC1. Having a procedure for controlling NKCC1 protein expression opens the doors for therapeutic interventions for diseases involving the mis-regulation or depletion of NKCC1 proteins, for example during aging.

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

    Directory of Open Access Journals (Sweden)

    Thomas Unger

    2004-03-01

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

  8. Sex differences and central protective effect of 17beta-estradiol in the development of aldosterone/NaCl-induced hypertension.

    Science.gov (United States)

    Xue, Baojian; Badaue-Passos, Daniel; Guo, Fang; Gomez-Sanchez, Celso E; Hay, Meredith; Johnson, Alan Kim

    2009-05-01

    The present study tested the hypotheses that male and female rats respond differently to subcutaneous infusions of aldosterone (Aldo; 1.8 microg.kg(-1).h(-1), 1% NaCl to drink; 28 days) and that central estrogen plays a protective role against the development of hypertension. In rats with blood pressure (BP) and heart rate (HR) measured by Data Sciences International telemetry, chronic Aldo/NaCl treatment induced a greater increase in BP in males (Delta25.4 +/- 2.4 mmHg) than in females (Delta7.1 +/- 2.2 mmHg). Gonadectomy augmented Aldo/NaCl-induced hypertension in females (Delta18.2 +/- 2.0 mmHg) but had no effect in males (Delta23.1 +/- 2.9 mmHg). Immunohistochemistry for Fra-like activity was higher in the paraventricular nucleus of intact males, castrated males, and ovariectomized (OVX) females compared with intact females after 28 days of Aldo/NaCl treatment. In intact males, central 17beta-estradiol (E(2)) inhibited the Aldo/NaCl increase in BP (Delta10.5 +/- 0.8) compared with that in central vehicle plus systemic Aldo/NaCl (Delta26.1 +/- 2.5 mmHg) rats. Combined administration of E(2) and estrogen receptor antagonist ICI182780 (ICI) blocked the protective effect of E(2) (Delta23.2 +/- 2.4 mmHg). In intact females central, but not peripheral, infusions of ICI augmented the Aldo/NaCl (Delta20.4 +/- 1.8 mmHg) BP increase. Finally, ganglionic blockade after Aldo infusions resulted in a smaller reduction in BP in intact females (-23.9 +/- 2.5 mmHg) and in central estrogen-treated males (-30.2 +/- 1.0 mmHg) compared with other groups (intact males, -39.3 +/- 3.4; castrated males, -41.8 +/- 1.9; intact males with central E(2) + ICI, -42.3 +/- 2.1; OVX females, -40.3 +/- 3.3; and intact females with central ICI, -39.1 +/- 1.3 mmHg). Chronic Aldo infusion produced increases in NaCl intake and decreases in HR that were both similar in all groups. Taken together, the results indicate that central estrogen plays a protective role in the development of Aldo

  9. Association of Aldosterone, Plasma Renin Activity (PRA and Superoxide Dismutase (SOD with Inflammation and Insulin Resistance in Adult Men with Central Obesity

    Directory of Open Access Journals (Sweden)

    Hera Yuliana Intantri

    2011-08-01

    Full Text Available BACKGROUND: Visceral Obesity is related with chronic low grade inflammation, and is the main component of metabolic syndrome (MetS. MetS is associated with increased cardiovascular disease (CVD. Furthermore, superoxide dismutase (SOD is correlated with insulin resistance. Several studies have reported a strong correlation between Renin Angiotensin Aldosterone System (RAAS and CVD, but the association of Aldosterone, Plasma Renin Activity (PRA and SOD with inflammation, insulin resistance and MetS have not been fully elucidated. The aim of this study was to investigate the correlation of Aldosterone, PRA, and SOD with inflammation (high sensitivity c-reactive protein/hsCRP and insulin resistance (homeostasis model assessment-insulin resistance/HOMA-IR in adult men with central obesity. METHODS: This was a cross-sectional study, which was carried out on 80 male subjects with central obesity who were divided into 2 groups: the group of subjects who had fulfilled the MetS criteria and the other group of subjects who did not. After an overnight fasting, blood pressure (BP was measured on all subjects and laboratory examinations were done for measurement of the concentration of fasting glucose, high density lipoprotein cholesterol (HDL-C, triglyceride, hsCRP, insulin, aldosterone, PRA, and SOD. RESULTS: We found aldosterone had positive correlation with PRA (r=0.389; p<0.001 and triglycerides (r=0.234; p=0.036. PRA had positive correlation with SOD (r=0.220; p=0.05 and HDL-C (r=0.273; p=0.014, but not with hsCRP (r=-0.044; p=0.696 and HOMA-IR (r=0.168 p=0.136. PRA correlated with HOMA-IR in MetS (r=0.471; p=0.01. Aldosterone and PRA were correlated with diastolic pressure in those with hypertension (r=0.680; p=0.003 and r=0.608; p=0.01. CONCLUSIONS: There is no direct correlation between aldosterone or SOD and Insulin resistance, and inflammation in men with central obesity. The correlation between PRA and MetS might be through insulin resistance

  10. Activation of peroxisome proliferator-activated receptor-γ coactivator 1α ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury.

    Science.gov (United States)

    Yuan, Yanggang; Huang, Songming; Wang, Wenyan; Wang, Yingying; Zhang, Ping; Zhu, Chunhua; Ding, Guixia; Liu, Bicheng; Yang, Tianxin; Zhang, Aihua

    2012-10-01

    Glomerular podocytes are highly specialized epithelial cells whose injury in glomerular diseases causes proteinuria. Since mitochondrial dysfunction is an early event in podocyte injury, we tested whether a major regulator of oxidative metabolism and mitochondrial function, the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), affects podocyte damage. Aldosterone-induced injury decreased PGC-1α expression, and induced mitochondrial and podocyte damage in dose- and time-dependent manners. The suppression of endogenous PGC-1α by RNAi caused podocyte mitochondrial damage and apoptosis while its increase by infection with an adenoviral vector prevented aldosterone-induced mitochondrial malfunction and inhibited injury. Overexpression of the silent mating type information regulation 2 homolog 1, a gene upstream of PGC-1α, prevented aldosterone-induced mitochondrial damage and podocyte injury by upregulating PGC-1α at both the transcriptional and post-translational levels. Resveratrol, a SIRT1 activator, attenuated aldosterone-induced mitochondrial malfunction and podocyte injury in vitro and in aldosterone-infused mice in vivo. Hence, endogenous PGC-1α may be important for maintenance of mitochondrial function in podocytes under normal conditions. Activators of SIRT1, such as resveratol, may be therapeutically useful in glomerular diseases to promote and maintain PGC-1α expression and, consequently, podocyte integrity.

  11. Diagnosis and treatment of primary aldosteronism%原发性醛固酮增多症的诊断与治疗

    Institute of Scientific and Technical Information of China (English)

    龚伟

    2012-01-01

    Primary aldosteronism is the most common cause of secondary hypertension. In the past, screening for primary aldosteronism was offered only in patients with hypertension associated with hypokalemia. Recent studies showed that hypokalemia was examined in only 25% of the patients with primary aldosteronism, which has increased the prevalence of primary aldosteronism to 10 15% of all cases with new onset hypertension. The article reviews the diagnosis and treatment of primary aldosteronism.%原发性醛固酮增多症(原醛症)是继发性高血压最常见的病因之一,以往通常只对低血钾的高血压患者进行原醛相关筛查.近期研究表明原醛症患者中仅25%可见低血钾表现,目前新发高血压患者中原醛症患者的发生率可达10% ~ 15%.本文就原醛症的诊断与治疗做一综述.

  12. Endocrine functional diagnosis in primary aldosteronism%原发性醛固酮增多症的内分泌功能诊断

    Institute of Scientific and Technical Information of China (English)

    张妮娅; 郑仁东; 刘超

    2012-01-01

    原发性醛固酮增多症(原醛症)是继发性高血压最常见的原因之一,以低肾素和高醛固酮血症为特征,血浆醛固酮/肾素比值(ARR)是筛查原醛症的可靠指标.而口服高钠负荷试验、生理盐水试验、氟氯可的松抑制试验或卡托普利试验中的任何一项均可作为ARR阳性患者的确诊试验;肾上腺静脉插管采血(AVS)是原醛症分型诊断的金标准.%Primary aldosteronism is one of the most common causes of secondary hypertension,which is characterized by low plasma renin and high aldosterone,and a major reliable tool for screening primary aldosteronism is the plasma aldosterone/renin activity ratio (ARR).Any of the four confirmatory tests such as oral sodium loading,intravenous saline infusion,captopril challenge and fludrocortisone administration plus sodium loading may carry out in patients who have positive ARR.And adrenal vein sampling (AVS) is recommended as the golden standard to diagnose primary aldosteronism.

  13. Effects of the nonpeptide V(1) vasopressin receptor antagonist SR49059 in hypertensive patients.

    Science.gov (United States)

    Thibonnier, M; Kilani, A; Rahman, M; DiBlasi, T P; Warner, K; Smith, M C; Leenhardt, A F; Brouard, R

    1999-12-01

    We assessed the clinical and pharmacological profile of the orally active V(1) vascular vasopressin (AVP) receptor nonpeptide antagonist SR49059 (SR) during the osmotic stimulation of AVP release in hypertensive patients. In a double-blind crossover-versus-placebo study, 24 untreated stage I or II essential hypertensive patients (12 whites and 12 blacks) received a single 300 mg oral dose of SR 2 hours before the stimulation of AVP secretion with a 5% hypertonic saline infusion. Hemodynamic, humoral, and hormonal parameters were monitored for up to 28 hours after drug administration. SR did not alter blood pressure or heart rate before the saline infusion and did not reduce the blood pressure increment induced by the hypertonic saline infusion. However, the blood pressure peak at the end of the hypertonic saline infusion was slightly lower in the presence of SR (P=0.04). Heart rate was significantly faster between 4 and 6 hours after SR administration (P=0.02). The rise in plasma sodium and osmolality triggered by the saline infusion was not modified by SR, but AVP release was slightly greater in the presence of SR (P<0.0003). AVP-induced aggregation of blood platelets in vitro was significantly reduced by SR, with a peak effect 2 hours after drug administration that coincided with the SR peak plasma concentration. Plasma renin activity and aldosterone before and after the saline infusion were not modified by SR. Urine volume and osmolality were not altered by SR administration. SR effects were similar in the 2 ethnic groups as well as in salt-sensitive versus salt-resistant patients. In a situation of AVP osmotic release and volume expansion in hypertensive patients, a single oral dose of the V(1) vascular AVP receptor nonpeptide antagonist SR49059, which is able to block AVP-induced platelet aggregation, exerts a transient vasodilation effect that is not associated with a sustained blood pressure reduction. SR49059 is a pure V(1) vascular receptor antagonist that

  14. mPGES-1 deletion impairs aldosterone escape and enhances sodium appetite.

    Science.gov (United States)

    Jia, Zhanjun; Aoyagi, Toshinori; Kohan, Donald E; Yang, Tianxin

    2010-07-01

    Aldosterone (Aldo) is a major sodium-retaining hormone that reduces renal sodium excretion and also stimulates sodium appetite. In the face of excess Aldo, the sodium-retaining action of this steroid is overridden by an adaptive regulatory mechanism, a phenomenon termed Aldo escape. The underlying mechanism of this phenomenon is not well defined but appeared to involve a number of natriuretic factors such prostaglandins (PGs). Here, we investigated the role of microsomal prostaglandin E synthase-1 (mPGES-1) in the response to excess Aldo. A 14-day Aldo infusion at 0.35 mg x kg(-1) x day(-1) via an osmotic minipump in conjunction with normal salt intake did not produce obvious disturbances in fluid metabolism in WT mice as suggested by normal sodium and water balance, plasma sodium concentration, hematocrit, and body weight, despite the evidence of a transient sodium accumulation on days 1 or 2. In a sharp contrast, the 14-day Aldo treatment in mPGES-1 knockoute (KO) mice led to increased sodium and water balance, persistent reduction of hematocrit, hypernatremia, and body weight gain, all evidence of fluid retention. The escaped wild-type (WT) mice displayed a remarkable increase in urinary PGE(2) excretion in parallel with coinduction of mPGES-1 in the proximal tubules, accompanied by a remarkable, widespread downregulation of renal sodium and water transporters. The increase in urinary PGE(2) excretion together with the downregulation of renal sodium and water transporters were all significantly blocked in the KO mice. Interestingly, compared with WT controls, the KO mice exhibited consistent increases in sodium and water intake during Aldo infusion. Together, these results suggest an important role of mPGES-1 in antagonizing the sodium-retaining action of Aldo at the levels of both the central nervous system and the kidney.

  15. Effect of nifedipine on plasma renin, aldosterone and catecholamines in arterial hypertension.

    Science.gov (United States)

    Pedersen, O L; Mikkelsen, E; Christensen, N J; Kornerup, H J; Pedersen, E B

    1979-05-21

    Acute sublingual administration of nifedipine 10--20 mg to 13 hypertensive patients caused a rapid decrease in blood pressure (BP) and a concomitant increase in heart rate (HR), plasma noradrenaline (NA) and plasma renin activity (PRA); there was no significant change in plasma adrenaline (A) or aldosterone (ALDO). Basal PRA was the major determinant of the rise in PRA, as a close correlation was present between the basal value and the increase caused by nifedipine (r = 0.92), p less than 0.001). The rise in PRA was also correlated with the plasma concentration of nifedipine after 60 min (r = 0.80, p less than 0.01), but it was not correlated with the decrease in BP, the rise in HR or the increase in NA. Nifedipine 30--60 mg daily for 6 weeks caused a reduction in mean BP from 133 to 113 mmHg (p less than 0.001). Body weight and serum potassium decreased but no consistent change was noted in NA, PRA, ALDO or 24 h-excretion of catecholamines. A significant correlation was present between the change in NA and that in PRA (r = 0.74, p less than 0.01). The alterations in the various parameters in the acute and chronic studies were not correlated. The findings indicate that different regulatory mechanisms are activated during acute and chronic administration of nifedipine. It is suggested that an initial rise in sympathetic activity gradually decreases during prolonged therapy, but it still remains a determinant of PRA.

  16. Effect of felodipine on myocardial and renal injury induced by aldosterone-high salt hypertension in uninephrectomized rats

    Directory of Open Access Journals (Sweden)

    B.B. Matsubara

    2010-05-01

    Full Text Available It has been recently shown that calcium channel blockers might have a protective effect on cardiac fibrogenesis induced by aldosterone. The objective of this study was to evaluate the protective effect of felodipine, a dihydropyridine calcium channel blocker, against heart and kidney damage caused by aldosterone-high sodium intake in uninephrectomized rats. Wistar rats were divided into three groups: CNEP (uninephrectomized + 1% NaCl in the drinking water, N = 9; ALDO (same as CNEP group plus continuous infusion of 0.75 µg/h aldosterone, N = 12; ALDOF (same as ALDO group plus 30 mg·kg-1·day-1 felodipine in the drinking water, N = 10. All results were compared with those of age-matched, untreated rats (CTL group, N = 10. After 6 weeks, tail cuff blood pressure was recorded and the rats were killed for histological analysis. Blood pressure (mmHg was significantly elevated (P < 0.05 in ALDO (180 ± 20 and ALDOF (168 ± 13 compared to CTL (123 ± 12 and CNEP (134 ± 13. Heart damage (lesion scores - median and interquartile range was 7.0 (5.5-8.0 in ALDO and was fully prevented in ALDOF (1.5; 1.0-2.0. Also, left ventricular collagen volume fraction (% in ALDOF (2.9 ± 0.5 was similar to CTL (2.9 ± 0.5 and CNEP (3.4 ± 0.4 and decreased compared to ALDO (5.1 ± 1.6. Felodipine partially prevented kidney injury since the damage score for ALDOF (2.0; 2.0-3.0 was significantly decreased compared to ALDO (7.5; 4.0-10.5, although higher than CTL (null score. Felodipine has a protective effect on the myocardium and kidney as evidenced by decreased perivascular inflammation, myocardial necrosis and fibrosis.

  17. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension

    DEFF Research Database (Denmark)

    Beuschlein, Felix; Boulkroun, Sheerazed; Osswald, Andrea

    2013-01-01

    Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na+/K+ ATPase α...... subunit) and ATP2B3 (encoding a Ca2+ ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced...... affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation...

  18. Auxin-Oxylipin Crosstalk: Relationship of Antagonists

    Institute of Scientific and Technical Information of China (English)

    Maik Hoffmann; Mathias Hentrich; Stephan Pollmann

    2011-01-01

    Phytohormones regulate a wide array of developmental processes throughout the life cycle of plants. Herein, the various plant hormones may interact additively, synergistically, or antagonistically. By their cooperation they create a delicate regulatory network whose net output largely depends on the action of specific phytohormone combinations rather than on the independent activities of separate hormones. While most classical studies of plant hormonal control have focused mainly on the action of single hormones or on the synergistic interaction of hormones in regulating various developmental processes, recent work is beginning to shed light on the crosstalk of nominally antagonistic plant hormones, such as gibberellins and auxins with oxylipins or abscisic acid. In this review, we summarize our current understanding of how two of the first sight antagonistic plant hormones, i.e. auxins and oxylipins,interact in controlling plant responses and development.

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

    Science.gov (United States)

    Mochel, Jonathan P; Danhof, Meindert

    2015-01-01

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

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

    Science.gov (United States)

    Morishita, Yoshiyuki; Kusano, Eiji

    2011-10-01

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

  1. Expression of Angiotensin Ⅱ Receptors in Aldosterone-producing Adenoma of the Adrenal Gland and Their Clinical Significance

    Institute of Scientific and Technical Information of China (English)

    吴准; 倪栋; 闫永吉; 李俊; 王保军; 欧阳金枝; 张国玺; 马鑫; 李宏召; 张旭

    2010-01-01

    The expression of angiotensin Ⅱ type 1 receptor (AT1R) and angiotensin Ⅱ type 2 receptor (AT2R) in aldosterone-producing adenoma (APA) of the adrenal gland was detected, and their relationship with clinical indexes of APA was analyzed. The mRNA expression of AT1R and AT2R in 50 cases of APA and tissues adjacent to tumors and 12 cases of normal adrenal tissues was detected by using reverse transcriptase polymerase chain reaction (RT-PCR). The expression of AT1R and AT2R proteins in paraffin-embedded slices o...

  2. Kidney transplant artery stenosis. Interrelationship between blood pressure, kidney function, renin-aldosterone system and body sodium content.

    Science.gov (United States)

    Kornerup, H J; Pedersen, E B; Fjeldborg, O

    1977-01-01

    Among 9 hypertensive recipients with kidney transplant artery stenosis (KTAS) evidence of increased activity of the renin system was present in 3. Surgical repair of KTAS in 4 recipients resulted in an increase in renal plasma flow and glomerular filtration rate associated with a decrease in exchangeable sodium and blood pressure. Peripheral plasma renin and aldosterone values were normal before and after operation in all. It is suggested that sodium retention may counterbalance increased activity of the renin system in KTAS. Preoperative determinations of plasma renin do not predict the effect of surgical repair of KTAS on hypertension.

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

    Science.gov (United States)

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

    2015-06-01

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

  4. Clinical analysis of spironolactone in treatment of primary aldosteronism%螺内酯治疗原发性醛固酮增多症临床分析

    Institute of Scientific and Technical Information of China (English)

    宁泽; 刘会峰; 解南

    2015-01-01

    Objective To investigate the clinical effect of spironolactone on primary aldosteronism.Methods The clinical data of 62 patients with primary aldosteronism disease were retrospectively analyzed.All patients received clinically conventional drug therapy combined with spironolactone.The urinary aldosterone, plasma aldosterone changes and incidence of adverse reactions before and after the treatment were recorded, and concluded by statistical analysis.Results After sixty-two patients with primary aldosteronism used spironolactone based on the conventional therapy, the urinary aldosterone and plasma aldosterone levels decreased compared with before treatment, the differences were significant (P < 0.05).Conclusions The clinical efficacy of spironolactone combined with conventional treatment on patients with primary aldosteronism is satisfactory, and can effectively guarantee their quality of life and life safety.%目的 探讨螺内酯治疗原发性醛固酮增多症的临床应用效果.方法 对62例原发性醛固酮增多症患者临床资料进行回顾性分析,所有患者均经临床常规药物联合螺内酯治疗.记录其治疗前后尿醛固酮、血浆醛固酮变化情况及不良反应发生率,给予统计学分析后得出结论.结果 62例原发性醛固酮增多症患者经常规治疗基础上加用螺内酯联合给药后,其尿醛固酮及血浆醛固酮检验水平均较治疗前有所下降,差异有统计学意义(P<0.05).结论 原发性醛固酮增多症患者经常规治疗基础上加入螺内酯联合给药可获得满意临床疗效,有效保障其生活质量及生命安全.

  5. Aberrant gonadotropin-releasing hormone receptor (GnRHR) expression and its regulation of CYP11B2 expression and aldosterone production in adrenal aldosterone-producing adenoma (APA).

    Science.gov (United States)

    Nakamura, Yasuhiro; Hattangady, Namita G; Ye, Ping; Satoh, Fumitoshi; Morimoto, Ryo; Ito-Saito, Takako; Sugawara, Akira; Ohba, Koji; Takahashi, Kazuhiro; Rainey, William E; Sasano, Hironobu

    2014-03-25

    Aberrant expression of gonadotropin-releasing hormone receptor (GnRHR) has been reported in human adrenal tissues including aldosterone-producing adenoma (APA). However, the details of its expression and functional role in adrenals are still not clear. In this study, quantitative RT-PCR analysis revealed the mean level of GnRHR mRNA was significantly higher in APAs than in human normal adrenal (NA) (P=0.004). GnRHR protein expression was detected in human NA and neoplastic adrenal tissues. In H295R cells transfected with GnRHR, treatment with GnRH resulted in a concentration-dependent increase in CYP11B2 reporter activity. Chronic activation of GnRHR with GnRH (100nM), in a cell line with doxycycline-inducible GnRHR (H295R-TR/GnRHR), increased CYP11B2 expression and aldosterone production. These agonistic effects were inhibited by blockers for the calcium signaling pathway, KN93 and calmidazolium. These results suggest GnRH, through heterotopic expression of its receptor, may be a potential regulator of CYP11B2 expression levels in some cases of APA.

  6. Genetic factors influencing pyrimidine-antagonist chemotherapy

    NARCIS (Netherlands)

    Maring, JG; Groen, HJM; Wachters, FM; Uges, DRA; de Vries, EGE

    2005-01-01

    Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of

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

    Science.gov (United States)

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

    2013-11-01

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

  8. The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels.

    Science.gov (United States)

    van Leeuwen, Nienke; Caprio, Massimiliano; Blaya, Carolina; Fumeron, Frédéric; Sartorato, Paola; Ronconi, Vanessa; Giacchetti, Gilberta; Mantero, Franco; Fernandes-Rosa, Fabio L; Simian, Christophe; Peyrard, Sévrine; Zitman, Frans G; Penninx, Brenda W J H; de Kloet, E Ron; Azizi, Michel; Jeunemaitre, Xavier; Derijk, Roel H; Zennaro, Maria-Christina

    2010-11-01

    The mineralocorticoid receptor (MR) is essential in the regulation of volemia and blood pressure. Rare mutations in the MR gene cause type 1 pseudohypoaldosteronism and hypertension. In this study we characterized the common MR polymorphism c.-2G>C (rs2070951) in vitro and tested its influence on parameters related to blood pressure regulation and the renin-angiotensin system. In vitro studies showed that the G allele was associated with decreased MR protein levels and reduced transcriptional activation compared with the C allele. Association studies were performed with several outcome variables in 3 independent cohorts: a mild hypertensive group subjected to a salt-sensitivity test, a healthy normotensive group included in a crossover study to receive both a high and low Na/K diet, and a large cohort (The Netherlands Study of Depression and Anxiety), in which blood pressure was measured. Subjects with the GG genotype had significantly higher plasma renin levels both in the mild hypertensive group and in normal volunteers compared with homozygous C carriers. The GG genotype was also correlated with higher plasma aldosterone levels in healthy subjects. In both the mild hypertensive group and The Netherlands Study of Depression and Anxiety cohort the genotype GG was associated with higher systolic blood pressure in males. In conclusion, the G allele of the common functional genetic polymorphism c.-2G>C in the MR gene associates with increased activation of the renin-angiotensin-aldosterone axis and with increased blood pressure, probably related to decreased MR expression.

  9. Plasma catecholamines, renin and aldosterone during combined alpha- and beta- adrenoceptor blockade in patients with severe arterial hypertension.

    Science.gov (United States)

    Kornerup, H J; Pedersen, E B; Pedersen, A; Pedersen, G; Christensen, N J

    1980-01-01

    Arterial blood pressure and plasma catecholamines, renin activity and aldosterone concentration in 12 patients with severe essential hypertension were studied before and after combined alpha- and beta- adrenoceptor blockade induced by oral labetalol treatment for 2 months. Frusemide in a fixed dose was employed as a basic antihypertensive agent throughout the study. Blood pressure was adequately controlled in only 6 patients. Mean body weight increased by 1.8 kg and there was a rise in body weight which was inversely correlated with the fall in standing mean blood pressure. The mean plasma noradrenaline concentration decreased from 0.30 to 0.20 ng/ml, whereas plasma adrenaline did not change significantly. Plasma renin activity and aldosterone concentration varied greatly, but the mean values did not change significantly. Change in body weight was correlated inversely with changes in plasma noradrenaline and renin. The results suggest that labetalol, through its combined alpha- and beta- adrenoceptor blocking action, induces a rise in body weight, probably due to sodium and fluid retention, which partly counterbalances its anti-hypertensive effect and partly modifies both renin and sympathetic nervous activity.

  10. A case of primary selective hypoaldosteronism carrying three mutations in the aldosterone synthase (Cyp11b2) gene.

    Science.gov (United States)

    Taranta, Anna; Bizzarri, Carla; Masotti, Andrea; Sciré, Giuseppe; Pampanini, Valentina; Cappa, Marco

    2012-05-25

    An infant with a clinical phenotype of early onset hypoaldosteronism has been screened for mutation analysis of the Cyp11b2 gene encoding aldosterone synthase enzyme. We have described a novel nonsense mutation in exon 3 (c.508C>T) that gave rise to a shorter protein (Q170X) and two known concurrent missense mutations (c.594A>C in exon 3 and c.1157T>C in exon 7) that led to substitution of glutamic acid for aspartic acid at amino acid position 198 (E198D) and of valine for alanine at amino acid position 386 (V386A). The father, who carried E198D plus V386A mutations, showed a fractional sodium excretion of 1.25% that was unmodified by dietary salt restriction, suggesting a mild haploinsufficiency. We examined by in silico analysis the effect of the mutations on the secondary and tertiary structures of aldosterone synthase to explain the inefficient enzymatic activity. The Q170X mutation produced a truncated protein, which was consequently associated with a loss of catalytic activity. As predicted by JPred web system and Dock 6.3 software, the concurrent expression of E198D and V386A mutations induced a significant secondary structure rearrangement and a shift of the heme group and the 18-hydroxycorticosterone substrate from their optimal placement.

  11. Unmasked renal impairment and prolonged hyperkalemia after unilateral adrenalectomy for primary aldosteronism coexisting with primary hyperparathyroidism: report of a case.

    Science.gov (United States)

    Hibi, Yatsuka; Hayakawa, Nobuki; Hasegawa, Midori; Ogawa, Kimio; Shimizu, Yoshimi; Shibata, Masahiro; Kagawa, Chikara; Mizuno, Yutaka; Yuzawa, Yukio; Itoh, Mitsuyasu; Iwase, Katsumi

    2015-02-01

    We herein report the case of a patient with critical hyperkalemia after unilateral adrenalectomy (ADX) for aldosterone-producing adenomas, which were coexisting with primary hyperparathyroidism. A right adrenal tumor oversecreting mineral corticoid was identified in a 62-year-old female whose kidney function had been impaired due to primary hyperaldosteronism and hyperparathyroidism. The ADX improved her hypertension with normalization of the plasma aldosterone concentration, but without adequately increasing her plasma renin activity. Her eGFR further decreased postoperatively, hyperkalemia appeared and the serum potassium level rose to 6.3 mEq/L at 3 months after ADX. Then, treatment with calcium polystyrene sulfonate jelly was started. Eight months after ADX, a left lower parathyroidectomy was performed, and the serum calcium and intact parathyroid hormone levels decreased to the normal range. The hyperkalemia was difficult to control within 20 months postoperatively without treatment with calcium polystyrene sulfonate jelly or hydrocortisone. This suggests that unmasking the renal impairment and relative hypoaldosteronism after ADX might induce critical hyperkalemia.

  12. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit+ bosentan group and Nit+ losartan group. Nitroglycerin tolerance was induced by 2-day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg- 1· d- 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg- 1· d- 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit+ losartan group and Nit+ bosentan group compared with Nit group [(31.95± 4.45 ) % vs (21.00± 3.69 ) % , P Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance .

  13. Renin-angiotensin-aldosterone responsiveness to low sodium and blood pressure reactivity to angiotensin-II are unrelated to cholesteryl ester transfer protein mass in healthy subjects

    NARCIS (Netherlands)

    Krikken, Jan A.; Dallinga-Thie, Geesje M.; Navis, Gerjan; Dullaart, Robin P. F.

    2008-01-01

    Background: The blood pressure increase associated with the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib is probably attributable to an off-target effect but it is unknown whether activation of the renin-angiotensin-aldosterone system (RAAS) may be related to variation in the pla

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

    Science.gov (United States)

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

    2000-01-01

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

  15. Sodium restriction on top of renin-angiotensin-aldosterone system blockade increases circulating levels of N-acetyl-seryl-aspartyl-lysyl-proline in chronic kidney disease patients

    NARCIS (Netherlands)

    Kwakernaak, Arjan J.; Waanders, Femke; Slagman, Maartje C. J.; Dokter, Martin M.; Laverman, Gozewijn D.; de Boer, Rudolf A.; Navis, Gerjan

    2013-01-01

    Objective:Sodium restriction potentiates the efficacy of the rennin-angiotensin-aldosterone system (RAAS)-blockade and improves long-term cardiovascular and renal protection, even independent of the better blood pressure control. The mechanisms underlying the potentiation of cardiorenal protection b

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

    NARCIS (Netherlands)

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

    2016-01-01

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

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

    NARCIS (Netherlands)

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

    2016-01-01

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

  18. Influence of insulin on plasma concentration and renal excretion of sodium and potassium in normal, electrolytes depleted and aldosterone treated dogs.

    Science.gov (United States)

    Bak, M; Szczepańska-Sadowska, E; Krzymień, J; Kozłowski, S; Czyzyk, A

    1987-10-01

    Effects of insulin on plasma concentration and renal excretion of sodium and potassium were compared in conscious dogs 1) maintained in water and electrolytes balance (Series 1, 10 dogs), 2) depleted of electrolytes by repeated i.v. loading with 20% mannitol (Series 2, 10 dogs), and 3) aldosterone treated (0.8 micrograms.kg-1.h-1 i.v., Series 3, 10 dogs). In each Series intravenous infusion of insulin at a rate of 0.05 U.kg-1.h-1 elicited transient increase in plasma sodium concentration and prolonged hypokalemia. Repeated loading with mannitol in Series 2 elicited significant elevation of plasma sodium, ADH and aldosterone concentrations, as well as decrease in extracellular fluid volume. Infusion of insulin in this Series elicited smaller decrease in plasma potassium concentration and longer lasting hypernatremia than in dogs in water-electrolytes balance. Aldosterone infusion in Series 3 did not change hypokalemic effect of insulin but attenuated hypernatremia. Infusion of insulin in Series 1 elicited increase of sodium excretion and decrease in potassium excretion. These effects were absent in Series 2 and 3. The results indicate that depletion of electrolytes and blood aldosterone elevation modify the effects of insulin on plasma concentration and renal excretion of sodium and potassium.

  19. Role of voltage-gated calcium channels in the regulation of aldosterone production from zona glomerulosa cells of the adrenal cortex.

    Science.gov (United States)

    Barrett, Paula Q; Guagliardo, Nick A; Klein, Peter M; Hu, Changlong; Breault, David T; Beenhakker, Mark P

    2016-10-15

    Zona glomerulosa cells (ZG) of the adrenal gland constantly integrate fluctuating ionic, hormonal and paracrine signals to control the synthesis and secretion of aldosterone. These signals modulate Ca(2+) levels, which provide the critical second messenger to drive steroid hormone production. Angiotensin II is a hormone known to modulate the activity of voltage-dependent L- and T-type Ca(2+) channels that are expressed on the plasma membrane of ZG cells in many species. Because the ZG cell maintains a resting membrane voltage of approximately -85 mV and has been considered electrically silent, low voltage-activated T-type Ca(2+) channels are assumed to provide the primary Ca(2+) signal that drives aldosterone production. However, this view has recently been challenged by human genetic studies identifying somatic gain-of-function mutations in L-type CaV 1.3 channels in aldosterone-producing adenomas of patients with primary hyperaldosteronism. We provide a review of these assumptions and challenges, and update our understanding of the state of the ZG cell in a layer in which native cellular associations are preserved. This updated view of Ca(2+) signalling in ZG cells provides a unifying mechanism that explains how transiently activating CaV 3.2 channels can generate a significant and recurring Ca(2+) signal, and how CaV 1.3 channels may contribute to the Ca(2+) signal that drives aldosterone production.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  1. Mineralocorticoid and glucocorticoid receptor antagonists in animal models of anxiety

    NARCIS (Netherlands)

    Korte, SM; KorteBouws, GAH; Koob, GF; DeKloet, ER; Bohus, B

    1996-01-01

    The behavioral effects of intracerebroventricular (ICV) administration of a specific mineralocorticoid receptor (MR) antagonist [RU28318 (10-50 ng/2 mu l)], a glucocorticoid receptor (GR) antagonist [RU38486 (1-50 ng/2 mu l)], or both antagonists (50 ng/2 mu l), were studied in two different animal

  2. High affinity retinoic acid receptor antagonists: analogs of AGN 193109.

    Science.gov (United States)

    Johnson, A T; Wang, L; Gillett, S J; Chandraratna, R A

    1999-02-22

    A series of high affinity retinoic acid receptor (RAR) antagonists were prepared based upon the known antagonist AGN 193109 (2). Introduction of various phenyl groups revealed a preference for substitution at the para-position relative to the meta-site. Antagonists with the highest affinities for the RARs possessed hydrophobic groups, however, the presence of polar functionality was also well tolerated.

  3. Novel benzimidazole-based MCH R1 antagonists.

    Science.gov (United States)

    Carpenter, Andrew J; Al-Barazanji, Kamal A; Barvian, Kevin K; Bishop, Michael J; Britt, Christy S; Cooper, Joel P; Goetz, Aaron S; Grizzle, Mary K; Hertzog, Donald L; Ignar, Diane M; Morgan, Ronda O; Peckham, Gregory E; Speake, Jason D; Swain, Will R

    2006-10-01

    The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.

  4. [Cutaneous adverse effects of TNFalpha antagonists].

    Science.gov (United States)

    Failla, V; Sabatiello, M; Lebas, E; de Schaetzen, V; Dezfoulian, B; Nikkels, A F

    2012-01-01

    The TNFalpha antagonists, including adalimumab, etanercept and infliximab, represent a class of anti-inflammatory and immunosuppressive drugs. Although cutaneous adverse effects are uncommon, they are varied. There is no particular risk profile to develop cutaneous adverse effects. The principal acute side effects are injection site reactions and pruritus. The major long term cutaneous side effects are infectious and inflammatory conditions. Neoplastic skin diseases are exceptional. The association with other immunosuppressive agents can increase the risk of developing cutaneous adverse effects. Some adverse effects, such as lupus erythematosus, require immediate withdrawal of the biological treatment, while in other cases temporary withdrawal is sufficient. The majority of the other cutaneous adverse effects can be dealt without interrupting biologic treatment. Preclinical and clinical investigations revealed that the new biologics, aiming IL12/23, IL23 and IL17, present a similar profile of cutaneous adverse effects, although inflammatory skin reactions may be less often encountered compared to TNFalpha antagonists.

  5. Blockades of angiotensin and aldosterone reduce osteopontin expression and interstitial fibrosis infiltration in rats with myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yu-ling; ZHOU Shu-xian; LEI Juan; YUAN Gui-yi; WANG Jing-feng

    2008-01-01

    Background It has been reported that osteopontin has an important role in cardiac fibrosis and remodeling.However,its direct mechanisms remain unclear.The purpose of this study was to investigate the role of angiotensin and aldosterone blockades in cardiac osteopontin expression associated with cardiac remodeling in myocardial infarcted (MI) rats.Methods Fifty SD rats that survived 24 hours after ligating left anterior descending coronary artery were randomly divided into three groups:Ml-saline group (n=15,5 ml/d),MI-perindopril group (n=18,perindopril 2 mg·kg-1·d-1) and MI-spironolacton (n=17,spironolacton 20 mg·kg-1.d-1).A sham operation group (n=15) was selected as non-infarcted control.At 6 weeks after treatment,hemodynamic pararmeters and left ventricular function were measured with catheterization,interstitial fibrosis infiltration and cardiomyocyte diameters were evaluated histologically.Myocardium osteopontin protein expression level in the non-infarcted myocardium was detected by Western blotting.Results No osteopontin protein was detected in the myocardium of sham-operation rats.High levels of osteopontin protein expression were detected in the MI-saline rats,but the levels were suppressed in the MI-perindopril and MI-spironolacton rats at 6 weeks following MI (P<0.01,respectively).Compared with the sham operation group,all rats in the MI group showed marked interstitial fibrosis infiltration in the non-infarction area,higher ventricular weight]body weight ratio,significantly increased cardiomyocyte diameter (P<0.01,respectively),and developed significant systolic and diastolic dysfunction as indicated by decreased left ventricular systolic pressure (LVSP) and ±dp/dt,as well as increased left ventricular end-diastolic pressure (LVEDP) (P<0.01,respectively).Angiotensin and aldosterone blockades partly prevented cardiac fibrosis and systolic and diastolic dysfunction (P<0.01,respectively).Conclusion Treatment with angiotensin and aldosterone blockades

  6. Development of adrenal zonation in fetal rats defined by expression of aldosterone synthase and 11beta-hydroxylase.

    Science.gov (United States)

    Wotus, C; Levay-Young, B K; Rogers, L M; Gomez-Sanchez, C E; Engeland, W C

    1998-10-01

    The adult rat adrenal cortex is comprised of three concentric steroidogenic zones that are morphologically and functionally distinguishable: the zona glomerulosa, zona intermedia, and the zona fasciculata/reticularis. Expression of the zone-specific steroidogenic enzymes, cytochrome P450 aldosterone synthase (P450aldo), and P450 11beta hydroxylase (P45011beta), produced by the zona glomerulosa and zona fasciculata/reticularis, respectively, can be used to define the adrenal cortical cell phenotype of these two zones. In this study, immunohistochemistry and in situ hybridization were used to determine the ontogeny of expression of P450aldo and P45011beta to monitor the pattern of development of the rat adrenal cortex. RIA was used to measure adrenal content of aldosterone and corticosterone, the resulting products of the two enzymatic pathways. Double immunofluorescent staining for both enzymes at gestational day 16 (E16) showed P45011beta protein expressed in cells distributed throughout most of the adrenal intermixed with a separate, but smaller, population of cells expressing P450aldo protein. Whereas expression of P45011beta protein retained a similar pattern of distribution from E16 to adulthood (ignoring distribution of SA-1 positive, presumptive medullary cells), P450aldo protein changed its pattern of distribution by E19, becoming localized in a discontinuous ring of cells adjacent to the capsule. By postnatal day 1, P450aldo protein distribution was similar to that observed in adult glands; P450aldo-positive cells formed a continuous zone underlying the capsule. In situ hybridization showed that the pattern of P45011beta messenger RNA expression paralleled protein expression at all times, whereas P450aldo messenger RNA paralleled protein at E19 and after, but was undetectable before E19. However, adrenal aldosterone and corticosterone, as measured by RIA, were detected by E16, supporting the functional capacity of both phenotypes for all ages studied. These

  7. Aminopyrimidine derivatives as adenosine antagonists / Janke Kleynhans

    OpenAIRE

    Kleynhans, Janke

    2013-01-01

    Aims of this project - The aim of this study was to design and synthesise novel 2-aminopyrimidine derivatives as potential adenosine A1 and A2A receptor antagonists. Background and rationale - Parkinson’s disease is the second most common neurodegenerative disorder (after Alzheimer’s disease) and is characterised by the selective death of the dopaminergic neurons of the nigro-striatal pathway. Distinctive motor symptoms include bradykinesia, muscle rigidity and tremor, while non-m...

  8. The Justification of Antagonistic Response to Wrongdoing

    OpenAIRE

    Goldman, David Michael

    2012-01-01

    There is a strong Western tradition of opposing angry, hostile, or antagonistic reactions to wrongdoing. In the twentieth century, leaders like Mahatma Gandhi and Dr. Martin Luther King, Jr. counseled responding to wrongdoing with forgiveness and love rather than anger, hate, or vindictiveness.This ideal has taken on an exalted status in Western culture. Gandhi and King are widely regarded as moral saints. And yet sometimes antagonism seems deeply appropriate. Consider a very serious wrong: s...

  9. Antagonistic parent-offspring co-adaptation.

    Directory of Open Access Journals (Sweden)

    Mathias Kölliker

    Full Text Available BACKGROUND: In species across taxa, offspring have means to influence parental investment (PI. PI thus evolves as an interacting phenotype and indirect genetic effects may strongly affect the co-evolutionary dynamics of offspring and parental behaviors. Evolutionary theory focused on explaining how exaggerated offspring solicitation can be understood as resolution of parent-offspring conflict, but the evolutionary origin and diversification of different forms of family interactions remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: In contrast to previous theory that largely uses a static approach to predict how "offspring individuals" and "parental individuals" should interact given conflict over PI, we present a dynamic theoretical framework of antagonistic selection on the PI individuals obtain/take as offspring and the PI they provide as parents to maximize individual lifetime reproductive success; we analyze a deterministic and a stochastic version of this dynamic framework. We show that a zone for equivalent co-adaptation outcomes exists in which stable levels of PI can evolve and be maintained despite fast strategy transitions and ongoing co-evolutionary dynamics. Under antagonistic co-adaptation, cost-free solicitation can evolve as an adaptation to emerging preferences in parents. CONCLUSIONS/SIGNIFICANCE: We show that antagonistic selection across the offspring and parental life-stage of individuals favors co-adapted offspring and parental behavior within a zone of equivalent outcomes. This antagonistic parent-offspring co-adaptation does not require solicitation to be costly, allows for rapid divergence and evolutionary novelty and potentially explains the origin and diversification of the observed provisioning forms in family life.

  10. Determinants and consequences of renal function variations with aldosterone blocker therapy in heart failure patients after myocardial infarction

    DEFF Research Database (Denmark)

    Rossignol, Patrick; Cleland, John G F; Bhandari, Sunil;

    2012-01-01

    We evaluated the effect of the selective mineralocorticoid receptor antagonist eplerenone on renal function and the interaction between changes in renal function and subsequent cardiovascular outcomes in patients with heart failure and left ventricular systolic dysfunction after an acute myocardi...

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

    Science.gov (United States)

    Tamargo, Juan; Caballero, Ricardo; Delpón, Eva

    2014-11-01

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

  12. Biosensor cell assay for measuring real-time aldosterone-induced release of histamine from mesenteric arteries

    DEFF Research Database (Denmark)

    Dalgaard, Emil G; Andersen, Kenneth; Svenningsen, Per

    2017-01-01

    as a sensitive biosensor assay for histamine release from isolated mouse mesenteric arteries. Activation of the H1 receptor by histamine was measured as an increased number of intracellular Ca(2+) transient peaks using fluorescence imaging RESULTS: The developed biosensor was sensitive to histamine...... in physiological relevant concentrations and responded to substances released by the artery preparation. Aldosterone treatment of mesenteric arteries from wild type mice for 50 minutes resulted in an increased number of intracellular Ca(2+) transient peaks in the biosensor cells, which was significantly inhibited...... by the histamine H1 blocker pyrilamine. Mesenteric arteries from mast cell deficient SASH mice induced similar pyrilamine-sensitive Ca(2+) transient response in the biosensor cells. Mesenteric arteries from wild type and SASH mice expressed histamine decarboxylase mRNA, indicating that mast cells are not the only...

  13. From the Cover: Glutamate antagonists limit tumor growth

    Science.gov (United States)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  14. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease

    DEFF Research Database (Denmark)

    Currie, Gemma; Taylor, Alison H M; Fujita, Toshiro

    2016-01-01

    BACKGROUND: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease. Hyperkalaemi...

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

    Directory of Open Access Journals (Sweden)

    Annayya R Aroor

    2013-10-01

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

  16. Reduction of plasma aldosterone and arterial stiffness in obese pre- and stage1 hypertensive subjects after aerobic exercise

    Science.gov (United States)

    Collier, SR; Sandberg, K; Moody, AM; Frechette, V; Curry, CD; Ji, H; Gowdar, R; Chaudhuri, D; Meucci, M

    2017-01-01

    Obesity-related hypertension is associated with increased activity of the renin-angiotensin-aldosterone system (RAAS), increasing arterial stiffness. Aerobic exercise decreases pulse wave velocity (PWV), therefore a treatment option for hypertension and obesity. Assess RAAS activity and PWV before and after 4 weeks of aerobic training in unmedicated, pre-to-stage-1 hypertensives. Ten obese subjects (52±3.2 years, body mass index=33.5±1.4) performed 30 min of aerobic exercise on a treadmill 3 days per week at 65% of peak oxygen consumption (VO2peak). Descriptive characteristics, systolic and diastolic blood pressure (SBP and DBP), PWV, and a blood draw was performed at baseline, following the 4-week control and training interventions. No differences in descriptive characteristics during the control period were observed, however, a significant decrease in plasma aldosterone (ALDO) (255.4±75 to 215.8±66 pg ml−1, P=0.001), SBP (140±12 to 136±10.4 mm Hg; P=0.02), DBP (89±4.2 to 85±6.3 mm Hg; P =0.03) and central PWV (11.2±0.6 to 9.8±0.8 m s−1; P=0.04) was shown pre-to-post exercise training. Four weeks of moderate-intensity aerobic training in obese, hypertensives decreases plasma ALDO independently of body weight and is significantly correlated to decreases in PWV reductions. PMID:24785976

  17. Effect of exercise on plasma concentrations of arginine vasopressin, angiotensin II and aldosterone in hypertensive and normotensive renal transplant recipients.

    Science.gov (United States)

    Pedersen, E B; Danielsen, H; Nielsen, A H; Knudsen, F; Jensen, T; Kornerup, H J; Madsen, M

    1986-04-01

    Plasma concentrations of angiotensin II (A II), aldosterone (Aldo) and arginine vasopressin (AVP), and serum osmolality (Sosm) were determined before and after gradually increasing exercise loads on a bicycle ergometer in 10 hypertensive (group I) and 10 normotensive renal transplant recipients (group II), and in 15 healthy control subjects (group III). Working capacity was reduced in groups I and II. The A II, Aldo, AVP, Sosm increased in all groups after exercise. The A II was higher in group I than II and the percentage changes were significantly lower in groups I and II than in group III. There were no significant differences in Aldo between the groups either before or after exercise. The AVP was the same in groups I and II, and AVP in these groups was higher than in group III. The Sosm and AVP were significantly correlated in all groups. Neither A II, Aldo nor AVP were significantly correlated to systolic blood pressure (BP). Alterations in AVP, but not in A II or Aldo, were correlated to the degree of exercise load. It can be concluded that the renin-angiotensin-aldosterone system and the osmoregulatory system are stimulated during exercise in renal transplant recipients. The A II is elevated in post-renal transplant hypertension, but the responsiveness is reduced in both hypertensive and normotensive recipients. The alterations in AVP are probably secondary to changes in Sosm, and the higher AVP levels in recipients could be due to a decreased responsiveness of the renal tubules to AVP. Our findings are in good agreement with the hypothesis that hypertension after renal transplantation is angiotensin II-dependent.

  18. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    张建梅; 陈永红; 王晓红; 唐朝枢

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n =6, each): Control group, Nitroglycerin (Nit) group, Nit + bosentan group and Nit + losartan group. Nitroglycerin tolerance was induced by 2-day treatment ofnitroglycerin patch (0. 05mg/h). Angiotensin I1 receptor antagonist losartan (10mg ·kg-1·d-1) and endothe-lin receptor antagonist bosentan ( 100 mg·kg-1· d-1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group. The effec-tive percentages of hypotensive response to SNP were increased in both Nit + losartan group and Nit + bosentangroup compared with Nit group [(31.95±4.45) % vs (21.00±3.69) %, P <0.01and (33. 18±6. 16)% vs (21.00±3.69 ) %, P < 0. 01 , respectivelyl. The maximal vessel relaxation induced by SNP was thesame in 4 different groups but the highest EC50 (concentration which produces 50% of the maximal response toSNP) was found in tolerant group[ (34 ±10) nmol/L, P < 0. 01 ]. The ET-1 amounts in plasma and vasculartissue were markedly increased by 54% and 60% in Nit group compared with those in control group( P<0. 01). The ET-1 amounts in plasma and vascular tissue were decreased by 30% and 37% in Nit + losartangroup compared with those in Nit group ( P < 0.01 ). Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance.

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

    Science.gov (United States)

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

    2016-09-01

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

  20. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

    Science.gov (United States)

    Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E; Arons, Elena; Zaman, Paula; Polach, Kevin J; Matar, Majed; Yung, Lai-Ming; Yu, Paul B; Bowman, Frederick P; Opotowsky, Alexander R; Waxman, Aaron B; Loscalzo, Joseph; Leopold, Jane A; Maron, Bradley A

    2016-07-01

    Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth

  1. 原发性醛固酮增多症患者血钾水平的影响因素分析%Analysis of related factors of blood potassium in patients with primary aldosteronism

    Institute of Scientific and Technical Information of China (English)

    邓西元; 李航; 叶大伟

    2015-01-01

    目的:分析原发性醛固酮增多症患者血钾水平的影响因素。方法回顾性分析原发性醛固酮增多症患者82例临床资料,将其分为正常血钾组和低血钾组。探讨原发性醛固酮增多症患者血钾与其血醛固酮、肾素、血管紧张素域及醛固酮肾素活性比值(ARR)的关系。结果原发醛固酮增多症患者血钾与醛固酮肾素活性比值(ARR)有相关性(P<0.05),正常血钾组与低血钾组ARR值差异有统计学意义(P<0.05)。结论在原发性醛固酮增多症患者中,醛固酮肾素活性比值反映其血钾水平。%Objective To analyse the related factors of blood potassium in patients with primary aldosteronism. Meth-ods Clinical date of 82 patients with primary aldosteronism were retrospectively analyzed. They were divided into normal blood potassium group and low blood potassium group, analysed the relationship of blood potassium with serum aldosterone, plasma renin activity, angiotensin II and aldosterone/plasma renin activity ratio (ARR). Results Blood potassium of patients with primary aldosteronism was significantly correlated with aldosterone/plasma renin activity ratio. There was statistical difference in ARR value between normal blood potassium group and low blood potassium group. Conclusion Aldosterone/plasma renin ac-tivity ratio reflects its potassium level in patients with primary aldosteronism.

  2. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels;

    2015-01-01

    A high degree of structural heterogeneity of the GABAA receptors (GABAARs) has been revealed and is reflected in multiple receptor subtypes. The subunit composition of GABAAR subtypes is believed to determine their localization relative to the synapses and adapt their functional properties...... to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...

  3. Antioxidant effects of calcium antagonists in rat brain homogenates.

    Science.gov (United States)

    Yao, K; Ina, Y; Nagashima, K; Ohmori, K; Ohno, T

    2000-06-01

    We studied the antioxidant activities of calcium antagonists against autoxidation in rat brain homogenates. The homogenates were incubated for 30 min at 37 degrees C with or without a calcium antagonist and subsequently assayed for lipid peroxide content. Percent inhibition of the lipid peroxidation was used as an index of the antioxidant effect. Dihydropyridine calcium antagonists exhibited concentration-dependent (3-300 micromol/l) inhibitory effects against lipid peroxidation. The relative order of antioxidant potency and associated IC50 values (micromol/l) of the calcium antagonists for inhibition of the lipid peroxidation were as follows: nifedipine (51.5)>barnidipine (58.6)>benidipine (71.2)>nicardipine (129.3)>amlodipine (135.5)>nilvadipine (167.3)>nitrendipine (252.1)> diltiazem (>300)=verapamil (>300). These results suggest that some dihydropyridine calcium antagonists show antioxidant properties. The antioxidant effects of the calcium antagonists may contribute to their pharmacological actions.

  4. Sexually antagonistic selection in human male homosexuality.

    Directory of Open Access Journals (Sweden)

    Andrea Camperio Ciani

    Full Text Available Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness, accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait.

  5. Sexually antagonistic selection in human male homosexuality.

    Science.gov (United States)

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-06-18

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait.

  6. Activins and activin antagonists in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Alev Deli; Emanuel Kreidl; Stefan Santifaller; Barbara Trotter; Katja Seir; Walter Berger; Rolf Schulte-Hermann; Chantal Rodgarkia-Dara; Michael Grusch

    2008-01-01

    In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo-or heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic co-receptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.

  7. ETA-receptor antagonists or allosteric modulators?

    DEFF Research Database (Denmark)

    De Mey, Jo G R; Compeer, Matthijs G; Lemkens, Pieter

    2011-01-01

    The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects. In resista......The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects....... In resistance arteries, the long-lasting contractile effects can only be partly and reversibly relaxed by low-molecular-weight ET(A) antagonists (ERAs). However, the neuropeptide calcitonin-gene-related peptide selectively terminates binding of ET1 to ET(A). We propose that ET1 binds polyvalently to ET(A......) and that ERAs and the physiological antagonist allosterically reduce ET(A) functions. Combining the two-state model and the two-domain model of GPCR function and considering receptor activation beyond agonist binding might lead to better anti-endothelinergic drugs. Future studies could lead to compounds...

  8. Zebrafish phenotypic screen identifies novel Notch antagonists.

    Science.gov (United States)

    Velaithan, Vithya; Okuda, Kazuhide Shaun; Ng, Mei Fong; Samat, Norazwana; Leong, Sze Wei; Faudzi, Siti Munirah Mohd; Abas, Faridah; Shaari, Khozirah; Cheong, Sok Ching; Tan, Pei Jean; Patel, Vyomesh

    2017-04-01

    Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27(KIP1). Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

  9. Evaluation of H2 receptor antagonists in chronic idiopathic urticaria

    Directory of Open Access Journals (Sweden)

    Minocha Y

    1995-01-01

    Full Text Available H1-antagonist (hydroxyzine hydrochloride in dosage of 10 mg-25 mg thrice a day failed to elicit satisfactory response in 60 out of 170 patients of chronic idiopathic urticaria. Additional administration of H2-antagonist (cimetidine in dosage of 200 mg four times a day, in patients not responding earlier to H1-antagonist alones exhibited moderate to good improvement of various parameters of urticaria in approximately 85% patients

  10. Human primary aldosteronism: from clinical observations to in-vivo and ex-vivo studies on the pressor effects of Urotensin II

    OpenAIRE

    menegolo, mirko

    2013-01-01

    In a patient affected by primary aldosteronism we have identified the presence of a pheochromocytoma not secreting catecholamines. The analysis of the transcriptome in the pheochromocytoma revealed a high expression of Urotensin II (UII). UII is a somatostatin-like cyclic 11-aminoacid vasoconstrictor peptide, first identified in the teleost fish caudal-neuro-secretory system and then in humans, that has been demonstrated to be a potent vasoactive peptide involved in the physiology and path...

  11. Advance of research on application of renin-angiotensin-aldosterone system blockers in elderly patients with chronic kidney disease%RAAS阻滞剂在老年慢性肾脏病中应用的研究进展

    Institute of Scientific and Technical Information of China (English)

    张琪; 倪兆慧

    2014-01-01

    全球老龄人(年龄≥65岁)所占的人口比例正逐步上升。老年人由于其特殊的生理状态更易被一些慢性病如,高血压、糖尿病、慢性肾脏病( CKD)所困扰。肾素-血管紧张素-醛固酮系统( RAAS)的过分活跃可导致高血压、心血管事件及CKD的发生。因此,针对RAAS的治疗具有可行性。但老年患者在使用RAAS阻滞剂[主要包括血管紧张素转换酶抑制剂( ACEI)、血管紧张素受体阻滞剂( ARB)、肾素抑制剂、醛固酮拮抗剂]类药物时更易出现肾小球滤过率( GFR)下降、高钾血症、低血压等不良反应,所以临床使用时,需要特别平衡使用该类药物的利弊。尽管目前对老年人使用RAAS阻滞剂药物有限的研究大多获得了肯定的结论,但是,仍需要更多、更长周期的研究结果来探寻老年CKD患者使用RAAS阻滞剂的疗效和安全性,以及是否确实能减缓CKD的进展。%Theproportionofglobalolderpeople(age≥65years)isgraduallyincreasing.Because of their special physiological state,older people are more easily troubled by some chronic diseases such as hypertension,diabetes,and chronic kidney disease( CKD). Overactivity of renin-angiotensin-aldosterone system( RAAS)can lead to hypertension,cardiovascular events,as well as CKD. Therefore,the treatment targeting RAAS is feasible. However,while using RAAS blockers including angiotensin converting enzyme inhibitors( ACEI),angiotensin receptor blockers( ARB),renin inhibitors,and aldosterone antagonists, elderly patients are more likely to be subjected to decrease of glomerular filtration rate ( GFR ), hyperkalemia,and hypotension,etc,indicating that it is specially required to weigh the pros and cons before clinical use of such drugs. Although most limited researches on efficacy of RAAS blocker drugs in elderly patients obtained positive conclusions,more long-term studies are still needed to explore the therapeutic efficacy

  12. Case Report: A case report of acromegaly associated with primary aldosteronism [v1; ref status: indexed, http://f1000r.es/2ny

    Directory of Open Access Journals (Sweden)

    Joanna Matrozova

    2014-02-01

    Full Text Available We describe a patient with a rare combination of acromegaly and primary aldosteronism. A 37 year-old female patient was diagnosed with acromegaly on the basis of typical clinical, hormonal and image characteristics. She presented also with one of the most common co-morbidities – arterial hypertension. The patient has been regularly followed-up and after three surgical interventions, irradiation and adjuvant treatment with a dopamine agonist, acromegaly was finally controlled in 2008 (20 years after diagnosis. Arterial hypertension however, remained a therapeutic problem even after prescription of four antihypertensive drugs. She had normal biochemical parameters, except for low potassium levels 3.2 (3.5-5.6 mmol/l. This raised the suspicion of primary hyperaldosteronism, confirmed by a high aldosterone to plasma rennin activity ratio, high aldosterone level after a Captopril challenge test and visualization of a 35 mm left adrenal nodule on a CT scan. After an operation, the patient recovered from hypokalemia and antihypertensive therapy was reduced to a small dose of a Ca blocker. Co-morbid arterial hypertension is common in acromegaly, though it is rare for this to be caused by Conn’s adenoma. The association of Conn’s adenoma with acromegaly has been interpreted in two lines: as a component of multiple endocrine neoplasia type (MEN1 syndrome or as a direct mitogenic effect of hyperactivated GH-IGF1 axis.

  13. AMP-activated protein kinase inhibits TGF-β-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition.

    Science.gov (United States)

    Lee, Jang Han; Kim, Ji Hyun; Kim, Ja Seon; Chang, Jai Won; Kim, Soon Bae; Park, Jung Sik; Lee, Sang Koo

    2013-03-15

    The epithelial-mesenchymal transition (EMT) is a novel mechanism that promotes renal fibrosis. Transforming growth factor-β (TGF-β), angiotensin II, aldosterone, high glucose, and urinary albumin are well-known causes of EMT and renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed EMT induced by the above agents in tubular epithelial cells. All experiments were performed using HK-2 cells. Protein expression was measured by Western blot analysis. Intracellular reactive oxygen species (ROS) were analyzed by flow cytometry. Exposure of tubular cells to TGF-β (10 ng/ml), angiotensin II (1 μM), aldosterone (100 nM), high glucose (30 mM), and albumin (5 mg/ml) for 5 days induced EMT, as shown by upregulation of α-smooth muscle actin and downregulation of E-cadherin. ROS and NADPH oxidase 4 (Nox4) expression were increased, and antioxidants such as tiron and N-acetylcysteine inhibited EMT induction. Metformin (the best known clinical activator of AMPK) suppressed EMT induction through inhibition of ROS via induction of heme oxygenase-1 and endogenous antioxidant thioredoxin. An AMPK inhibitor (compound C) and AMPK small interfering RNA blocked the effect of metformin, and another AMPK activator [5-aminoimidazole-4-carboxamide-1β riboside (AICAR)] exerted the same effects as metformin. In conclusion, AMPK activation might be beneficial in attenuating the tubulointerstitial fibrosis induced by TGF-β, angiotensin II, aldosterone, high glucose, and urinary albumin.

  14. Simultaneous measurement of aldosterone and cortisol by high-performance liquid chromatography-tandem mass spectrometry: application to dehydration-rehydration studies.

    Science.gov (United States)

    Taylor, Paul J; van Rosendal, Simon P; Coombes, Jeff S; Gordon, Richard D; Stowasser, Michael

    2010-05-01

    Aldosterone and cortisol are useful biomarkers of dehydration and stress, respectively. The aim of this study was to develop an HPLC-tandem mass spectrometric method for the simultaneous measurement of aldosterone and cortisol in human plasma that could be applied to the study of athletes undergoing exercise and rehydration. Samples were prepared and analysed using an on-line sample preparation/HPLC system coupled to a triple quadrupole tandem-mass spectrometer. Samples (200 microL) were pre-treated and extracted on Hysphere C18 HD cartridges (7 microm, Spark Holland). Chromatography was performed on a Sunfire C18 analytical column (50 mm x 3.0 mm, 3 microm, Waters) under isocratic conditions at a flow rate of 0.3 mL/min. The mobile phase consisted of 35% acetonitrile/water. Mass spectrometric detection was by selected reaction monitoring using negative electrospray ionization conditions. The assay had an analytical range of 25-500 pg/mL and 25-500 ng/mL for aldosterone and cortisol, respectively (r(2)>0.992, n=22). Inter-day accuracy and imprecision for quality control samples was 99.4-106% and dehydration, rehydration and exercise when measured by this method. The reported method is suitable to facilitate the study of athletes undergoing dehydration and rehydration protocols.

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

    Science.gov (United States)

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

    2015-11-01

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

  16. NP-59 SPECT/CT Imaging in Stage 1 Hypertensive and Atypical Primary Aldosteronism: A 5-Year Retrospective Analysis of Clinicolaboratory and Imaging Features

    Directory of Open Access Journals (Sweden)

    Yi-Chun Chen

    2013-01-01

    Full Text Available Objective. We retrospectively analyzed all primary aldosteronism (PA patients undergoing NP-59 SPECT/CT imaging with regard to their clinicolaboratory and imaging features, investigation, and outcomes. Material and Methods. 11 PA patients who presented to our hospital for NP-59 SPECT/CT imaging between April 2007 and March 2012 and managed here were analyzed. Results. Among 11 PA patients, eight (73% had stage 1 hypertension, three (27% stage 2 hypertension, four (36% normal plasma aldosterone concentration, nine (82% nonsuppressed plasma renin activity (PRA, six (55% normal aldosterone-renin-ratio (ARR, eight (73% serum potassium ≧3 mEq/L, seven (64% subclinical presentation, seven (64% negative confirmatory testing, and four (36% inconclusive results on CT scan and seven (64% on planar NP-59 scan. All 11 (100% patients had positive results on NP-59 SPECT/CT scan. Two (18% met typical triad and nine (82% atypical triad. Among nine atypical PA patients, three (33% had clinical presentation, six (67% subclinical presentation, six (67% negative confirmatory testing, and four (44% inconclusive results on CT scan and six (67% on planar NP-59 scan. All patients had improved outcomes. Significant differences between typical and atypical PA existed in PRA and ARR. Conclusions. NP-59 SPECT/CT may provide diagnostic potential in stage 1 hypertensive and atypical PA.

  17. Case Report: A case report of acromegaly associated with primary aldosteronism [v2; ref status: indexed, http://f1000r.es/3ke

    Directory of Open Access Journals (Sweden)

    Joanna Matrozova

    2014-06-01

    Full Text Available We describe a patient with a rare combination of acromegaly and primary aldosteronism. A 37 year-old female patient was diagnosed with acromegaly on the basis of typical clinical, hormonal and image characteristics. She presented also with one of the most common co-morbidities – arterial hypertension. The patient has been regularly followed-up and after three surgical interventions, irradiation and adjuvant treatment with a dopamine agonist, acromegaly was finally controlled in 2008 (20 years after diagnosis. Arterial hypertension however, remained a therapeutic problem even after prescription of four antihypertensive drugs. She had normal biochemical parameters, except for low potassium levels 3.2 (3.5-5.6 mmol/l. This raised the suspicion of primary hyperaldosteronism, confirmed by a high aldosterone to plasma rennin activity ratio, high aldosterone level after a Captopril challenge test and visualization of a 35 mm left adrenal nodule on a CT scan. After an operation, the patient recovered from hypokalemia and antihypertensive therapy was reduced to a small dose of a Ca blocker. Co-morbid arterial hypertension is common in acromegaly, though it is rare for this to be caused by Conn’s adenoma. The association of Conn’s adenoma with acromegaly has been interpreted in two lines: as a component of multiple endocrine neoplasia type (MEN1 syndrome or as a direct mitogenic effect of hyperactivated GH-IGF1 axis.

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

    Science.gov (United States)

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

    2016-06-23

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

  19. 原发性醛固酮增多症遗传学研究进展%Genetics advances in primary aldosteronism

    Institute of Scientific and Technical Information of China (English)

    谢利芳; 欧阳金芝; 母义明

    2015-01-01

    原发性醛固酮增多症(primary aldosteronism,PA)是一种常见的、可治愈的继发性高血压的原因之一,主要由醛固酮瘤(aldosterone-producing adenoma,APA)或特发性醛固酮增多症(idiopathic hyperaldosteronism,IHA)引起,只有小部分的PA是家族性醛固酮增多症(familial hyperaldosteronism,FH)。基因组学技术的发展,使得人们逐步阐明了与APA、IHA和FH发生有关的部分异常基因。本文主要描述了与PA有关的异常基因,以期为PA分型诊断和继发性高血压的治疗提供新的方向。%Primary aldosteronism (PA) is the most common and curable form of secondary hypertension which is primarily caused by either aldosterone-producing adenoma (APA) or by idiopathic hyperaldosteronism (IHA). Only a tiny part of PA patients are familial hyperaldosteronism (FH). Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities of APA, IHA and FH. In this review, we mainly describe the genetic abnormalities associated with PA and may offer a new direction for diagnosis of PA and treatment in secondary hypertension.

  20. Increased plasma aldosterone-to-renin ratio is associated with impaired left ventricular longitudinal functional reserve in patients with uncomplicated hypertension.

    Science.gov (United States)

    Choi, Eui-Young; Ha, Jong-Won; Yoon, Se-Jung; Shim, Chi-Young; Seo, Hye-Sun; Park, Sungha; Ko, Young-Guk; Kang, Seok-Min; Choi, Donghoon; Rim, Se-Joong; Jang, Yangsoo; Chung, Namsik

    2008-03-01

    Relative aldosterone excess is associated with endothelial dysfunction and higher incidence of end organ damage. We sought to investigate whether plasma aldosterone-to-renin ratio (ARR) is associated with left ventricular (LV) longitudinal function reserve to exercise in patients with controlled hypertension. In the patients with controlled and uncomplicated hypertension without overt LV hypertrophy, plasma aldosterone concentrations (ng/dL) and renin activities (ng/mL/h) were measured. Then 28 consecutive patients with higher ARR (group II, ARR > or = 30, 55 +/- 10 years) and 56 age- and sex-matched patients with lower ARR (group I, ARR reserve at 25-W and 50-W exercise, defined as DeltaE' (change from resting E', cm/s) of group II was significantly lower than that of group I (2.60 +/- 1.42 vs 1.85 +/- 1.44 cm/s, P = .016; 3.40 +/- 1.48 vs 2.36 +/- 1.43 cm/s, P = .003, respectively). In conclusion, in patients with hypertension without overt LV hypertrophy, increased ARR is associated with increased LV mass, and impaired LV longitudinal functional reserve during exercise.

  1. Renin–angiotensin–aldosterone system related gene polymorphisms and urinary total arsenic is related to chronic kidney disease

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Wei-Jen [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Huang, Ya-Li [Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Shiue, Horng-Sheng [Department of Chinese Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan (China); Chen, Tzen-Wen [Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan (China); Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Lin, Yuh-Feng [Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei, Taiwan (China); Huang, Chao-Yuan [Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan (China); Lin, Ying-Chin [Department of Family Medicine, Shung Ho Hospital, Taipei Medical University, New Taipei, Taiwan (China); Department of Health Examination, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan (China); Division of Family Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan (China); Han, Bor-Cheng [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Hsueh, Yu-Mei, E-mail: ymhsueh@tmu.edu.tw [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China)

    2014-09-01

    A recent study demonstrated that an increased risk of chronic kidney disease (CKD) was associated with high urinary total arsenic levels. However, whether genomic instability is related to CKD remains unclear. An association between CKD and genetic polymorphisms of regulation enzymes of the renin–angiotensin–aldosterone system (RAAS), such as angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AT1R), and aldosterone synthase (CYP11B2) has not been shown. The aim of the present study was to investigate the relationship between arsenic, genetic polymorphisms of RAAS enzymes and CKD. A total of 233 patients and 449 age- and gender-matched controls were recruited from the Taipei Medical University Hospital, Taipei Municipal Wan Fang Hospital and the Shin Kong Wu Ho-Su Memorial Hospital. Concentrations of urinary arsenic were determined by a high-performance liquid chromatography-linked hydride generator, and atomic absorption spectrometry. Polymorphisms of ACE(I/D), AGT(A[− 20]C), (T174M), (M235T), AT1R(A1166C) and CYP11B2(C[− 344]T) were examined by polymerase chain reaction and restriction fragment length polymorphism. Subjects carrying the CYP11B2 TT genotype had a higher odds ratio (OR), 1.39 (0.96–2.01), of CKD; while those with the AGT(A[− 20]C) CC genotype had an inverse OR of CKD (0.20 (0.05–0.81)), and a high-risk genotype was defined as A/A + A/C for AGT(A[− 20C]) and T/T for CYP11B2(C[− 344]T). The trend test showed a higher OR for CKD in patients who had either high urinary total arsenic levels or carried the high-risk genotype, or both, compared to patients with low urinary total arsenic levels, who carried the low-risk genotype, and could also be affected by the hypertension or diabetes status. - Highlights: • AGT(− 20 C) and CYP11B2(− 344 T) genotypes were significantly associated with CKD. • Combined effect of high-risk genotypes and high urinary total arsenic on OR of CKD. • Combined

  2. On the top of ARB N/L type Ca channel blocker leads to less elevation of aldosterone

    Science.gov (United States)

    Konoshita, Tadashi; Kaeriyama, Saori; Urabe, Machi; Nakaya, Takahiro; Yamada, Mika; Ichikawa, Mai; Yamamoto, Katsushi; Sato, Satsuki; Imagawa, Michiko; Fujii, Miki; Makino, Yasukazu; Zenimaru, Yasuo; Wakahara, Shigeyuki; Suzuki, Jinya; Ishizuka, Tamotsu; Nakamura, Hiroyuki

    2016-01-01

    The activation of the renin–angiotensin system (RAS) is one of the unfavourable characteristics of calcium channel blocker (CCB). N type calcium channel is thought to be involved in renin gene transcription and adrenal aldosterone release. Accordingly, N/L type CCB has a possibility of less elevation of plasma aldosterone concentrations (PAC) among CCBs. In a monotherapy study, we had already demonstrated that N/L type CCB leads to less activation of the RAS compared with L type CCB. The objective of this study is to substantiate the hypothesis that at the condition of additive administration on the top of an angiotensin receptor blocker (ARB), still N/L type CCB leads to less elevation of PAC compared with L type one. Subjects were 60 hypertensives administered with valsartan. As an open label study, amlodipine (L type) or cilnidipine (N/L type) were administered on the top of valsartan (ARB) in a cross-over manner. Results were as follows (valsartan+amlodipine compared with valsartan+cilnidipine): systolic blood pressure (SBP)/diastolic blood pressure (DBP) (mmHg): 132±10/76±10 compared with 131±10/77±9, P=0.95/0.48, plasma renin activity (PRA) (ng/ml·h): 2.41±2.67 compared with 2.00±1.50 P=0.20, PAC (pg/ml): 77.3±31.0 compared with 67.4±24.8, P<0.05, urinary albumin excretion (UAE) (mg/gCr): 105.9±216.1 compared with 73.9±122.2, P<0.05. Thus, PAC at cilnidipine was significantly lower than those at amlodipine in spite of the comparable BP reductions. Besides, UAE was significantly lower at cilnidipine. In conclusion, on the top of the ARB, it is suggested that cilnidipine administration might lead to less elevation of PAC and reduction in UAE compared with amlodipine. PMID:27515419

  3. Correlation between propranolol in plasma and urine, renin-aldosterone system and blood pressure in essential hypertension.

    Science.gov (United States)

    Pedersen, E B; Kornerup, H J; Pedersen, O L; Andreasen, F; Bjerregaard, P

    1981-01-01

    Thirty patients with mild or moderate essential hypertension, and a fixed elevation of diastolic blood pressure, were randomly allocated to three groups and treated with propranolol 40 mg x 4 (Group 1), 80 mg x 4 (group 2) and 160 mg x 4 (Group 3). Blood pressure (BP), pulse rate (PR), plasma renin activity (PRA), plasma aldosterone concentration (PAC), total plasma propranolol (tPP), free plasma propranolol (fPP), and 24 h urinary propranolol excretion (UP) were determined at the end of four consecutive periods: (A) after four weeks without any treatment; (B) after two to three weeks during which the propranolol dose was gradually increased to the intended level; (C) after four weeks, and (D) after eight weeks of unchanged treatment. The maximum reduction in diastolic BP occurred after period B, and in systolic BP after Period C, for Groups 2 and 3, and for all groups together; for Group 1, however, the maximum diastolic BP reduction was first seen after period C. PR was reduced to the same level in all groups after period B. After period B, PRA an PAC fell in all groups, and remained reduced during C and D Group 1. After periods C and D, PRA and PAC in Groups 2 and 3 did not differ significantly from the levels after period A; tPP, fPP and UP were significantly correlated with the propranolol dose, and were lowest in Group 1 and highest in Group 3; UP was negatively correlated with systolic but not diastolic BP in Periods B, C and D. In contrast neither fPP nor tPP were correlated with systolic or diastolic BP. There was no significant correlation between PRA, PAC and changes in PRA or PAC on the one hand and tPP, fPP, UP, BP or changes in BP on the other. It was concluded that propranolol effectively reduced BP, but diastolic BP reduction was most rapidly obtained at 320 and 640 mg daily, that the activity of the renin -aldosterone system was initially suppressed in all group, but for unknown reasons it increased towards the control level after seven to eleven

  4. Mutually-Antagonistic Interactions in Baseball Networks

    CERN Document Server

    Saavedra, Serguei; McCotter, Trent; Porter, Mason A; Mucha, Peter J

    2009-01-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit interesting structural changes over time. We also find that these networks exhibit a significant network structure that is sensitive to baseball's rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to compare the performance of players who competed under different conditions. We find that a player's position in the network does not correlate with his success in the random walker ranking but instead has a substantial effect on its sensitivity to changes in his own aggregate performance.

  5. Mutually-antagonistic interactions in baseball networks

    Science.gov (United States)

    Saavedra, Serguei; Powers, Scott; McCotter, Trent; Porter, Mason A.; Mucha, Peter J.

    2010-03-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit structural changes over time. We find interesting structure in the networks and examine their sensitivity to baseball’s rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to (1) compare the performance of players who competed under different conditions and (2) include information about which particular players a given player has faced. We find that a player’s position in the network does not correlate with his placement in the random walker ranking. However, network position does have a substantial effect on the robustness of ranking placement to changes in head-to-head matchups.

  6. Antagonists of IAP proteins as cancer therapeutics.

    Science.gov (United States)

    Dynek, Jasmin N; Vucic, Domagoj

    2013-05-28

    Inhibitor of apoptosis (IAP) proteins play pivotal roles in cellular survival by blocking apoptosis, modulating signal transduction, and affecting cellular proliferation. Through their interactions with inducers and effectors of apoptosis IAP proteins can effectively suppress apoptosis triggered by diverse stimuli including death receptor signaling, irradiation, chemotherapeutic agents, or growth factor withdrawal. Evasion of apoptosis, in part due to the action of IAP proteins, enhances resistance of cancer cells to treatment with chemotherapeutic agents and contributes to tumor progression. Additionally, IAP genes are known to be subject to amplification, mutation, and chromosomal translocation in human malignancies and autoimmune diseases. In this review we will discuss the role of IAP proteins in cancer and the development of antagonists targeting IAP proteins for cancer treatment.

  7. The Attractiveness of Opposites: Agonists and Antagonists.

    LENUS (Irish Health Repository)

    O'Brien, Tony

    2015-02-02

    ABSTRACT Opioid-induced bowel dysfunction, of which constipation is the most common aspect, is a major limiting factor in the use of opioids for pain management. The availability of an oral, long-acting formulation of oxycodone and naloxone represents a highly significant development in pain management. The combination of an opioid analgesic with an opioid antagonist offers reliable pain control with a significant reduction in the burden of opioid-induced constipation. This report is adapted from paineurope 2014; Issue 3, ©Haymarket Medical Publications Ltd, and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, LTD and is distributed free of charge to healthcare professionals in Europe. Archival issues can be accessed via the website: http:\\/\\/www.paineurope.com at which European health professionals can register online to receive copies of the quarterly publication.

  8. Antagonistic activity of marine sponges associated Actinobacteria

    Institute of Scientific and Technical Information of China (English)

    Selvakumar Dharmaraj; Dhevendaran Kandasamy

    2016-01-01

    Objective: To focus on the isolation and preliminary characterization of marine sponges associated Actinobacteria particularly Streptomyces species and also their antagonistic activities against bacterial and fungal pathogens. Methods: The sponges were collected from Kovalam and Vizhinjam port of south-west coast of Kerala, India. Isolation of strains was carried out from sponge extracts using international Streptomyces project media. For preliminary identification of the strains, morphological (mycelial colouration, soluble pigments, melanoid pigmentation, spore morphology), nutritional uptake (carbon utilisation, amonoacids influence, sodium chloride tolerance), physiological (pH, temperature) and chemotaxonomical characterization were done. Antimicrobial studies were also carried out for the selected strains. Results: With the help of the spicule structures, the collected marine sponges were identified as Callyspongia diffusa, Mycale mytilorum, Tedania anhelans and Dysidea fragilis. Nearly 94 strains were primarily isolated from these sponges and further they were sub-cultured using international Streptomyces project media. The strains exhibited different mycelial colouration (aerial and substrate), soluble and melanoid pigmentations. The strains possessed three types of sporophore morphology namely rectus flexibilis, spiral and retinaculiaperti. Among the 94 isolates, seven exhibited antibacterial and antifungal activities with maximal zone of inhibition of 30 mm. The nutritional, physiological and chemotaxonomical characteristic study helped in the conventional identification of the seven strains and they all suggest that the strains to be grouped under the genus Streptomyces. Conclusions: The present study clearly helps in the preliminary identification of the isolates associated with marine sponges. Antagonistic activities prove the production of antimicrobial metabolites against the pathogens. Marine sponges associated Streptomyces are universally well

  9. PARTIAL AGONISTS, FULL AGONISTS, ANTAGONISTS - DILEMMAS OF DEFINITION

    NARCIS (Netherlands)

    HOYER, D; BODDEKE, HWGM

    1993-01-01

    The absence of selective antagonists makes receptor characterization difficult, and largely dependent on the use of agonists. However, there has been considerable debate as to whether certain drugs acting at G protein-coupled receptors are better described as agonists, partial agonists or antagonist

  10. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology

    NARCIS (Netherlands)

    Al-Inany, Hesham G.; Youssef, Mohamed A.; Ayeleke, Reuben Olugbenga; Brown, Julie; Lam, Wai Sun; Broekmans, Frank J.

    2016-01-01

    Background: Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-oestrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists direct

  11. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    Science.gov (United States)

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  12. Optimisation of GnRH antagonist use in ART

    NARCIS (Netherlands)

    Hamdine, O.

    2014-01-01

    This thesis focuses on the optimisation of controlled ovarian stimulation for IVF using exogenous FSH and GnRH antagonist co-treatment, by studying the timing of the initiation of GnRH antagonist co-medication and the role of ovarian reserve markers in optimising ovarian response and reproductive ou

  13. Aldosterone induces aortic smooth muscle cell apoptosis%醛固酮诱导大鼠主动脉平滑肌细胞凋亡

    Institute of Scientific and Technical Information of China (English)

    闫永吉; 李炯明; 刘建和; 陈戬; 姜永明; 张劲松

    2012-01-01

    目的 观察醛固酮在体内能否诱导主动脉平滑肌细胞凋亡.方法 将24只SD大鼠随机分为3组,每组8只:(1)空白溶剂设为对照组;(2)醛固酮组;(3)醛固酮+血管扩张剂组.渗透泵内分别注入醛固酮(1 μg/h)或空白溶剂,然后埋于大鼠背部皮下.肼苯哒嗪[25 mg/(kg·d)]溶于引用水,每日灌胃1次.8周后脱氧核苷酸末端转移介导的缺口末端标记法(TUNEL)检测凋亡的主动脉平滑肌细胞.结果 醛固酮组和醛固酮+血管扩张剂组大鼠主动脉TUNEL阳性的平滑肌细胞分别占(18.0±1.5)%和(16.5±2.0)%,与对照组(4.7±1.0)%比较,差异有统计学意义(P<0,05);后两组之间差异无统计学意义(P>0.05).结论 醛固酮在体内可以直接诱导主动脉平滑肌细胞凋亡.%Objective To determine whether aldosterone induces aortic smooth muscle cell apoptosis in vivo.Methods 24 Sprague-Dawley rats were randomly divided into 3 groups:vehicle as control; aldosterone and aldosterone plus hydralazine.All animals were then implanted with an osmotic mini-pump containing either aldosterone ( 1 μg/h) or vehicle.Hydralazine [ 25 mg/(kg·d) ] was resolved in drinking water and gavaged once daily.After 8 weeks,aortic smooth muscle cell (ASMC) apoptosis was examined by terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay.Results TUNEL-positive aortic smooth muscle cells in aldosterone-infused and aldosterone plus hydralazine rats were ( 18.0± 1.5 ) % and ( 16.5 ± 2.0) % respectively; compared with control rats (4.7 ± 1.0 ) %,there was signifi-cant difference (P < 0.05 ). In contrast,no significant difference was achieved between the latter twogroups (P > 0.05).Conclusion This study' s findings suggest that aldosterone induces aortic smooth muscle cell apoptosis by its direct effect on the aorta.

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

    Science.gov (United States)

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

    2012-10-01

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

  15. Effects of stress, circadian rhythms, and dietary sodium on brain cell-nuclear uptake of aldosterone and corticosterone

    Energy Technology Data Exchange (ETDEWEB)

    Yongue, B.G.

    1985-01-01

    The binding of the adrenal steroid hormones aldosterone (ALD) and corticosterone (CORT) in brain cell-nuclei has been implicated as a necessary step in the behavioral and physiological actions of these hormones. In vivo uptake of radioactively labeled ALD and CORT in adrenalectomized (ADX) rats indicates a strong cell-nuclear localization of both of these hormones in limbic brain regions (such as hippocampus, septum and amygdala). Research using sub-cellular fractionation and radioimmunoassay (RIA), has confirmed both the presence of endogenously secreted CORT in cell-nuclei and its limbic localization in the brains of adrenal-intact rats. In this study, environmental and dietary factors were manipulated to induce variation in serum ALD and CORT. A series of experiments employing sub-cellular fractionation and RIA were performed, which reveal that: (1) endogenously secreted ALD and CORT, are concentrated by cell-nuclei of the brain in adrenal-intact rats, (2) the majority of the corticosteroids measured in ethanol extracts of brain cell-nuclei are associated with receptor molecules, and (3) the regional distribution of endogenously secreted ALD differs markedly from the predominantly limbic pattern predicted from in vivo uptake of labeled ALD in ADX rats. Instead, brain cell-nuclear ALD is heavily concentrated in the hypothalamus, which supports the hypothesized relationship between the interaction of ALD and angiotensin in the brain and the behavioral regulation of fluid/electrolyte balance.

  16. Influence of season on plasma antidiuretic hormone, angiotensin II, aldosterone and plasma renin activity in young volunteers.

    Science.gov (United States)

    Kanikowska, Dominika; Sugenoya, Junichi; Sato, Maki; Shimizu, Yuuki; Inukai, Yoko; Nishimura, Naoki; Iwase, Satoshi

    2010-05-01

    We investigated seasonal changes in hormonal and thermoregulatory responses. Eight volunteers were subjected to the experiment at four times of the year: around the vernal and autumnal equinoxes, and at the summer and winter solstices at latitude 35 degrees N. Plasma antidiuretic hormone (ADH), angiotensin II (ANG II), aldosterone (ALD) and plasma renin activity (PRA) were analyzed before and after water immersion. Seasonal changes in thermoregulatory responses were assessed by measuring core temperature and sweat rate during immersion of the leg in hot water (at 42 degrees C) for 30 min in a room maintained at 26 degrees C. The concentration of plasma ADH and ALD before water immersion was significantly higher in summer than in other seasons. The concentrations of ANG II and PRA did not show seasonal variations. Changes in tympanic temperature during water immersion showed significant differences between seasons, and were higher in winter than in other seasons. The sweat rate was significantly higher in summer than in other seasons. In summary, ADH and ALD concentrations displayed a seasonal rhythm with marked elevation in summer; this may be a compensative mechanism to prevent dehydration from increased sweat loss during summer due to heat acclimatization.

  17. Lower physical fitness in patients with primary aldosteronism is linked to the severity of hypertension and kalaemia.

    Science.gov (United States)

    Tuka, V; Matoulek, M; Zelinka, T; Rosa, J; Petrák, O; Mikeš, O; Krátká, Z; Štrauch, B; Holaj, R; Widimský, J

    2016-10-26

    Hypokalaemia as a typical feature of primary aldosteronism (PA) is associated with muscle weakness and could contribute to lower cardiopulmonary fitness. The aim of this study was to describe cardiopulmonary fitness and exercise blood pressure and their determinants during a symptom-limited exercise stress test in patients with PA. We performed a cross-sectional study of patients with confirmed PA who were included before adrenal vein sampling on whom a symptom-limited exercise stress test with expired gas analysis was performed. Patients were switched to the treatment with doxazosin and verapamil at least two weeks before the study. In 27 patients (17 male) the VO(2peak) was 25.4+/-6.0 ml/kg/min which corresponds to 80.8+/-18.9 % of Czech national norm. Linear regression analysis shows that VO(2peak) depends on doxazosin dose (DX) (p = 0.001) and kalaemia (p = 0.02): VO(2peak) = 4.2 - 1.0 * DX + 7.6 * Kalaemia. Patients with higher doxazosin doses had a longer history of hypertension and had used more antihypertensives before examination, thus indicating that VO(2peak) also depends on the severity of hypertension. In patients with PA, lower cardiopulmonary fitness depends inversely on the severity of hypertension and on lower plasma potassium level.

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

    Directory of Open Access Journals (Sweden)

    Maricica Pacurari

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-04-01

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

  20. EFFECT OF ELECTROACUPUNCTURE ON PLASMA ANGIOTENSIN-ALDOSTERONE AND ATRIAL NATRIURETIC POLYPEPTIDE IN RABBITS WITH ACUTE CEREBRAL INFARCTION

    Institute of Scientific and Technical Information of China (English)

    吴绪平; 王述菊; 刘玲; 周华

    2004-01-01

    Objective: To observe the therapeutic effect of electroacupuncture (EA) on plasma angiotensin (Ang*.Ⅱ), aldosterone (ALD) and atrial natriuretic polypeptide (ANP) contents in experimental cerebral infarction rabbits for analyzing the underlying mechanism of acupuncture in ameliorating blood supply of the brain tissue. Methods: A total of 80 rabbits were randomized into control (n=8), pseudo-operation (n=24), model (n=24) and EA (n=24) groups. Cerebral infarction model was established by infusion of self-thrombus into the carotid artery. EA (1 mA, 2 Hz) was applied to "Baihui"(百会GV 20) and "Shuigou"(水沟GV 26) for 30 min, once every 12 hours. Plasma Ang-II, ALD and ANP contents were detected with radioimmunoassay method. In the later 3 groups, blood samples were taken at 6 h, 24 h and 48 h after cerebral ischemia. Results: Compared with control and pseudo-operation groups, Ang-II and ALD contents of model group at 6 h, 24 h and 48 h after cerebral ischemia increased significantly while plasma ANP of the 3 time-courses of model group decreased considerably (P<0.01). In comparison with model group, results showed that Ang-II and ALD contents of EA group decreased significantly whereas ANP level of EA group increased strikingly (P<0.01). Conclusion: Electroacupuncture has the effects of raising plasma ANP level and lowering plasma Ang-II and ALD in cerebral infarction rabbits.

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

    Science.gov (United States)

    Thethi, Tina; Kamiyama, Masumi; Kobori, Hiroyuki

    2012-04-01

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

  2. 应用ROC曲线评价醛固酮肾素比值对原发性醛固酮增多症诊断的临床意义%Significance of aldosterone/plasma renin activity ratio in diagnosis of primary aldosteronism with ROC curve

    Institute of Scientific and Technical Information of China (English)

    邓西元; 庞欣欣; 张旭

    2011-01-01

    目的 应用接受者操作特性曲线(ROC曲线)选择术前诊断原发醛固酮增多症(原醛症)的醛固酮肾素比值(ARR)的最佳切点,并探讨醛固酮肾素比值在诊断原醛症方面的临床意义.方法 从2004年1月到2007年6月在同济医院行手术治疗的肾上腺肿瘤病例133例分为总原醛症组、醛固酮瘤组、肾上腺增生组和非原醛组,用ROC工作曲线选择醛固酮肾素比值的最佳切点.结果 总原醛症组和醛固酮瘤组的醛固酮肾素比值的最佳切点为40,而肾上腺增生组的最佳切点为20,醛固酮肾素比值与肾素活性(r=0.615,P<0.01)和血管紧张素Ⅱ(r=0.527,P<0.01)有负相关性.结论 运用醛固酮肾素比值来诊断原醛有很大价值,但还存在不足.%Objective To choose the best cut-off value and to evaluate the clinical significance of aldosterone/plasma renin activity ratio(ARR) for preoperative diagnosis of primary aldosteronism by ROC curve. Methods Data of 133 adrenal tumor cases treated surgically at Tongji Hospital from Jan. 2004 to June 2007 were retrospectively analyzed. The cases were divided into total primary aldosteronism group, APA group, adrenal hyperplasia group and non- primary aldosteronism group,and the best out-off value of ARR was detected by ROC. Results The best cut-off value of ARR was 40 in the total primary aldosteronism group and APA group, and was 20 in the adrenal hyperplasia group. The cut-off value of ARR was negatively correlated with plasma renin activity ratio( r= -0. 615 P<0. 01) and Angiotensin Ⅱ ( r= -0. 527 P<0.01) . Conclusions The use of ARR for diagnosis of primary aldosteronism is significant although it's not perfect.

  3. Fine Tuning of a Type 1 Interferon Antagonist.

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    Victoria Urin

    Full Text Available Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and enhanced binding to IFNAR2. Here, we further tune the IFN-1ant by producing three additional antagonists based on IFN-1ant but with altered activity profiles. We show that in all three cases the antiproliferative activity of interferons is blocked and the induction of gene transcription of immunomudolatory and antiproliferative associated genes are substantially decreased. Conversely, each of the new antagonists elicits a different degree of antiviral response, STAT phosphorylation and related gene induction. Two of the new antagonists promote decreased activity in relation to the original IFN-1ant, while one of them promotes increased activity. As we do not know the exact causes of the detrimental effects of IFNs, the four antagonists that were produced and analyzed provide the opportunity to investigate the extent of antagonistic and agonistic activity optimal for a given condition.

  4. Nalmefene: radioimmunoassay for a new opioid antagonist.

    Science.gov (United States)

    Dixon, R; Hsiao, J; Taaffe, W; Hahn, E; Tuttle, R

    1984-11-01

    A specific radioimmunoassay (RIA) has been developed for the quantitation of a new opioid antagonist, nalmefene, in human plasma. The method employs a rabbit antiserum to an albumin conjugate of naltrexone-6-(O-carboxymethyl)oxime and [3H]naltrexone as the radioligand. Assay specificity was achieved by extraction of nalmefene from plasma at pH 9 into ether prior to RIA. The procedure has a limit of sensitivity of 0.2 ng/mL of nalmefene using a 0.5-mL sample of plasma for analysis. The intra- and interassay coefficients of variation did not exceed 5.6 and 11%, respectively. The specificity of the RIA was established by demonstrating excellent agreement (r = 0.99) with a less sensitive and more time consuming HPLC procedure in the analysis of clinical plasma samples. The use of the RIA for the pharmacokinetic evaluation of nalmefene is illustrated with plasma concentration profiles of the drug in humans following intravenous and oral administration.

  5. Antagonistic Neural Networks Underlying Differentiated Leadership Roles

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    Richard Eleftherios Boyatzis

    2014-03-01

    Full Text Available The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950’s. Recent research in neuroscience suggests that the division between task oriented and socio-emotional oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks -- the Task Positive Network (TPN and the Default Mode Network (DMN. Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success.

  6. 血浆醛固酮/肾素活性比值在原发性醛固酮增多症诊断中的价值%The Diagnosis Value of Plasma Aldosterone/renin Activity Ratio in Primary Aldosteronism

    Institute of Scientific and Technical Information of China (English)

    刘慧光; 任建伟; 陈彦民

    2011-01-01

    目的:探讨血浆醛固酮/肾素活性比值(ARR)在原发性醛固酮增多症(PA)诊断中的临床价值.方法:选择我院收治的高血压患者460例,空腹采血后采用放射免疫法测定患者醛固酮和肾素水平,并计算血浆醛固酮/肾素活性比值.对其中疑诊为原发性醛固酮增多症的患者再行肾上腺薄层CT扫描,并行血液生化和血清钾检测.结果:460例患者中,ARR>25者56例,经肾上腺薄层CT扫描、血液生化和血清钾检测后确诊为原发性醛固酮增多症者48例.ARR应用于原发性醛固酮增多症的检出率为10.43%,诊断符合率为85.71%.48例患者中合并低血钾者18例,占37.5%.结论:血浆醛固酮/肾素活性比值在临床的应用可使高血压人群中原发性醛固酮增多症的检出率明显增加,具有重要的临床价值,应作为重度高血压和难治性高血压患者的常规检查项目.%Objective: To investigate the diagnosis value of plasma aldosterone/renin activity ratio (ARR) in primary aldosteronism.Methods: 460 patients with hypertension were collected, after fasting blood measured by radioimmunoassay in patients with aldosterone and renin levels, and calculate the plasma aldosterone/renin activity ratio.Checking the patients which was suspected with primary aldosteronism by CT scan of adrenal thin, blood biochemistry and serum potassium.Results: In 460 patients, there were 56 patients' ARR>25.The CT scan, adrenal thin layer blood biochemical and potassium diagnosed after detecting primary aldosteronism in 48 cases.Detection rate was 10.43%, diagnostic rate was 85.71%.18 patients combined hypokalemia in 48 patients (37.5%).Conclusion: Plasma aldosterone/renin activity ratio in the clinical application can significantly increase the detection rate in hypertensives with primary aldosteronism, it has important clinical value, should be severe hypertension and refractory hypertension in patients with routine examination project.

  7. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists.

    Science.gov (United States)

    Khanfar, Mohammad A; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  8. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Mohammad eKhanfar

    2016-05-01

    Full Text Available With the very recent market approval of pitolisant (Wakix®, the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  9. Identification of a novel conformationally constrained glucagon receptor antagonist.

    Science.gov (United States)

    Lee, Esther C Y; Tu, Meihua; Stevens, Benjamin D; Bian, Jianwei; Aspnes, Gary; Perreault, Christian; Sammons, Matthew F; Wright, Stephen W; Litchfield, John; Kalgutkar, Amit S; Sharma, Raman; Didiuk, Mary T; Ebner, David C; Filipski, Kevin J; Brown, Janice; Atkinson, Karen; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel

    2014-02-01

    Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.

  10. New potential uroselective NO-donor alpha1-antagonists.

    Science.gov (United States)

    Boschi, Donatella; Tron, Gian Cesare; Di Stilo, Antonella; Fruttero, Roberta; Gasco, Alberto; Poggesi, Elena; Motta, Gianni; Leonardi, Amedeo

    2003-08-14

    A recent uroselective alpha(1)-adrenoceptor antagonist, REC15/2739, has been joined with nitrooxy and furoxan NO-donor moieties to give new NO-donor alpha(1)-antagonists. All the compounds studied proved to be potent and selective ligands of human cloned alpha(1a)-receptor subtype. Derivatives 6 and 7 were able to relax the prostatic portion of rat vas deferens contracted by (-)-noradrenaline because of both their alpha(1A)-antagonist and their NO-donor properties.

  11. Acutely elevated vasopressin increases circulating concentrations of cortisol and aldosterone in fasting northern elephant seal (Mirounga angustirostris) pups

    Science.gov (United States)

    Ortiz, Rudy M.; Wade, Charles E.; Ortiz, C. Leo; Talamantes, Frank

    2003-01-01

    The physiological actions of vasopressin (VP) in marine mammals are not well defined. To help elucidate its hormonal and renal effects in this group of mammals, northern elephant seal (Mirounga angustirostris) pups (N=7; 99+/-4 kg) were first infused with 0.9% saline (control; 220 ml), followed 24 h later with VP (as a 20 ng kg(-1) bolus, then 2 ng kg(-1) min(-1) for approximately 35 min in 225+/-16 ml saline). During both control and VP periods, blood samples were collected prior to infusion, and 15, 30, 60, 120 min and 24 h after infusion to examine the hormonal responses of the pups to VP. Renal responses were quantified from 24 h urine samples obtained prior to infusion (control) and 24 h post-infusion. Compared to the control period, infusion of VP increased plasma concentrations of cortisol over a 120 min period and aldosterone over 30 min, while plasma renin activity (PRA) was decreased for a 120 min period. The plasma urea:creatinine ratio was elevated following infusion of VP. Urine output and osmotic clearance were increased by 69+/-18% (mean +/- S.E.M.) and 36+/-10%, respectively, but free water clearance and glomerular filtration rate were not significantly altered 24 h post-infusion of VP. Solute (osmolality, Na(+), K(+) and Cl(-)) excretion and fractional excretion of electrolytes were also increased when compared to control values. The increase in cortisol concentration suggests that VP may possess corticotropin releasing hormone-like activity in elephant seals. If osmotic diuresis and natriuresis are typical consequences of elevated [VP] in fasting pups, then not increasing VP normally during the fast may serve as a protective mechanism to avoid the potential loss of Na(+) induced by elevated [VP]. Therefore, under natural fasting conditions, pups may be highly sensitive to small changes in [VP], resulting in the maintenance of water and electrolyte balance.

  12. Guanylyl cyclase/natriuretic peptide receptor-A gene disruption causes increased adrenal angiotensin II and aldosterone levels.

    Science.gov (United States)

    Zhao, Di; Vellaichamy, Elangovan; Somanna, Naveen K; Pandey, Kailash N

    2007-07-01

    Disruption of the guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA) gene leads to elevated arterial blood pressure and congestive heart failure in mice lacking NPRA. This study was aimed at determining whether Npr1 (coding for GC-A/NPRA) gene copy number affects adrenal ANG II and aldosterone (Aldo) levels in a gene-dose-dependent manner in Npr1 gene-targeted mice. Adrenal ANG II and Aldo levels increased in 1-copy mice compared with 2-copy mice, but decreased in 3-copy and 4-copy mice. In contrast, renal ANG II levels decreased in 1-copy (25%), 3-copy (38%), and 4-copy (39%) mice compared with 2-copy mice. The low-salt diet stimulated adrenal ANG II and Aldo levels in 1-copy (20 and 2,441%), 2-copy (15 and 2,339%), 3-copy (20 and 424%), and 4-copy (31 and 486%) mice, respectively. The high-salt diet suppressed adrenal ANG II and Aldo levels in 1-copy (46 and 29%) and 2-copy (38 and 17%) mice. On the other hand, the low-salt diet stimulated renal ANG II levels in 1-copy (45%), 2-copy (45%), 3-copy (59%), and 4-copy (48%) mice. However, the high-salt diet suppressed renal ANG II levels in 1-copy (28%) and 2-copy (27%) mice. In conclusion, NPRA signaling antagonizes adrenal ANG II and Aldo levels in a gene-dose dependent manner. Increased adrenal ANG II and Aldo levels may play an important role in elevated arterial blood pressure and progressive hypertension, leading to renal and vascular injury in Npr1 gene-disrupted mice.

  13. Prevalence of primary aldosteronism in patient's cohorts and in population-based studies--a review of the current literature.

    Science.gov (United States)

    Hannemann, A; Wallaschofski, H

    2012-03-01

    There is an ongoing controversy on the prevalence of primary aldosteronism (PA). We aimed to update a meta-analysis published in 2008, that compiled studies reporting the prevalence of positive ARR screening tests and PA. We therefore reviewed original studies published in 2008 or later to examine whether current reports provide similar, higher or lower prevalences of elevated ARRs or PA than reports included in the original meta-analysis. A systematic review of English articles using PubMed was conducted. Search and extraction of articles were performed by one review author; the second review author checked all extracted data. We identified 11 eligible studies. The updated, weighted mean prevalences of elevated ARRs and PA in primary care (prevalence of high ARRs 16.5%; prevalence of PA 4.3%) and referred patients (prevalence of high ARRs 19.6%; prevalence of PA 9.5%) were only marginally different from the mean values obtained in the original meta-analysis. Among the current studies the maximum values for the prevalence of elevated ARRs and PA were substantially lower than among the older studies. Our results confirm the main conclusions from the original meta-analysis. The prevalence of PA increases with the severity of hypertension and the inclusion of current study results did not alter the mean prevalences of elevated ARRs and PA in primary care and referred patients. Additionally, we found that current studies focus increasingly on patients in referral centers or special subgroups, while the prevalence of PA in the general hypertensive population is yet unknown.

  14. Baseline Serum Aldosterone-to-Renin Ratio is Associated with the Add-on Effect of Thiazide Diuretics in Non-Diabetic Essential Hypertensives

    Science.gov (United States)

    Huang, Chin-Chou; Leu, Hsin-Bang; Huang, Po-Hsun; Wu, Tao-Cheng; Lin, Shing-Jong; Chen, Jaw-Wen

    2013-01-01

    Background The baseline status of renin-angiotensin-aldosterone system (RAAS) might modify the blood pressure (BP) lowering effects of thiazide diuretics. This study aimed to determine if baseline RAAS indicated by serum aldosterone-to-renin ratio (ARR) could be associated with the add-on effects of thiazide on BP lowering in patients with other concomitant antihypertensive medication. Methods Non-diabetic hypertensive patients, either untreated or unsatisfactorily treated, were enrolled if their office systolic BP was ≥ 140 or diastolic BP ≥ 90 mmHg. After 2 weeks of diet control and lifestyle modification, patients with persistently elevated BP were prospectively given hydrochlorothiazide 50 mg daily for 2 weeks. Serum aldosterone-to-renin ratio (ARR) was determined before thiazide treatment. Patients with a significant (≥ 10%) reduction of office mean artery pressure (MAP) by thiazide treatment were defined as responders. Results Among the 66 patients studied, 27 were defined as responders after a 2-week hydrochlorothiazide treatment. Baseline serum renin level was reduced and ARR increased (p = 0.009) in the responders as compared with the non-responders. A similar pattern was also apparent in patients with or without concomitant medications. Furthermore, baseline renin level was inversely and ARR positively correlated to the MAP reduction both in the whole patient group and in patients with concomitant medications. By stepwise multiple linear regression analysis, ARR was the only independent predictor for the response to thiazide treatment (β = 0.051, p = 0.007). Conclusions Baseline ARR could be associated with the add-on effects of hydrochlorothiazide on BP reduction in patients with other concomitant antihypertensive treatment. PMID:27122683

  15. Comparison of stress-induced changes in adults and pups: is aldosterone the main adrenocortical stress hormone during the perinatal period in rats?

    Directory of Open Access Journals (Sweden)

    János Varga

    Full Text Available Positive developmental impact of low stress-induced glucocorticoid levels in early development has been recognized for a long time, while possible involvement of mineralocorticoids in the stress response during the perinatal period has been neglected. The present study aimed at verifying the hypothesis that balance between stress-induced glucocorticoid and mineralocorticoid levels is changing during postnatal development. Hormone responses to two different stressors (insulin-induced hypoglycaemia and immune challenge induced by bacterial lipopolysaccharid measured in 10-day-old rats were compared to those in adults. In pups corticosterone responses to both stressors were significantly lower than in adults, which corresponded well with the stress hyporesponsive period. Importantly, stress-induced elevations in aldosterone concentration were significantly higher in pups compared both to corticosterone elevations and to those in adulthood with comparable adrenocorticotropin concentrations in the two age groups. Greater importance of mineralocorticoids compared to glucocorticoids in postnatal period is further supported by changes in gene expression and protein levels of gluco- (GR and mineralocorticoid receptors (MR and selected enzymes measured by quantitative PCR and immunohystochemistry in the hypothalamus, hippocampus, prefrontal cortex, liver and kidney. Gene expression of 11beta-hydroxysteroid dehydrogenase 2 (11β-HSD2, an enzyme enabling preferential effects of aldosterone on mineralocorticoid receptors, was higher in 10-day-old pups compared to adult animals. On the contrary, the expression and protein levels of GR, MR and 11β-HSD1 were decreased. Presented results clearly show higher stress-induced release of aldosterone in pups compared to adults and strongly suggest greater importance of mineralocorticoids compared to glucocorticoids in stress during the postnatal period.

  16. Clinical value of posture test in subtype differentiation of primary aldosteronism%体位试验对鉴别原发性醛固酮增多症分型的价值

    Institute of Scientific and Technical Information of China (English)

    邢玉微; 邹俊杰; 石勇铨; 刘志民

    2016-01-01

    Objective To evaluate the value of posture test in the subtype differentiation of primary aldosteronism.Methods In total,91 patients with primary aldosteronism were divided into the aldosterone-producing adenoma (n =43)and idiopathic hyperaldosteronism groups (IHA,n =48).General characteris-tics,renin activity and aldosterone changes after posture test were statistically compared between two groups.Results Age,gender constitution,systolic and diastolic pressure and plasma potassium did not significantly differ between two groups (all P >0.05).Compared with IHA group,renin activity was significantly lower whereas aldosterone changes and the ratio of aldosterone /renin activity were significantly higher after saline ad-ministration in the aldosterone-producing adenoma group (all P 30% eleva-tion.In the IHA group,aldosterone level in a standing posture was elevated compared with that in a lying pos-ture including 8 cases with 30% elevation.The percentage of patients with 0.05).Conclusions Posture test contributes to directly identif-ying the aldosterone-producing adenoma with decreasing aldosterone level in a standing posture.For those with elevated aldosterone level after a standing posture,comprehensive tests are required to differentiate the subtype of primary aldosteronism.%目的:探讨体位试验对鉴别原发性醛固酮增多症分型的价值。方法将91例原发性醛固酮增多症患者分为醛固酮瘤组(43例)及特发性醛固酮增多症(IHA)组(48例),比较2组的一般特征及体位试验后肾素活性、醛固酮的变化特点。结果2组的年龄、性别构成比、收缩压、舒张压、血钾比较差异无统计学意义(P 均>0.05),醛固酮瘤组滴注生理盐水后肾素活性低于 IHA组,而滴注生理盐水后血浆醛固酮及醛固酮与肾素活性比值均高于 IHA 组(P 均<0.05)。体位试验显示醛固酮瘤组患者立位血浆醛固酮较卧位下降的有19例,升高的有24

  17. Influential factors on the ratio of plasma aldosterone concentration to plasma renin activity in screening primary aldosteronism%原发性醛固酮增多症筛查中血浆醛固酮/肾素活性比值的影响因素

    Institute of Scientific and Technical Information of China (English)

    鄞国书; 张少玲; 严励; 程桦

    2009-01-01

    The ratio of plasma aldosterone concentration to plasma renin activity (ARR) is a practical parameter in screening for primary aldosteronism (PA).However,variations of the cutoff value of ARR in different studies have been reported due to plenty of influential factors that may affect the secretions of renin and aldosterone. Lack of standardization of assays for ARR also makes direct comparisons among different studies difficult.The associated influential factors on ARR were introduced in this review.%血浆醛固酮水平/肾索活性比值(ARR)是筛查原发性醛固酮增多症的实用指标.由于影响肾素和醛同酮分泌的因素众多,ARR切点值变异范围较大,至今仍然是一个缺乏标准化的指标.本文综述这些因素,旨在临床上提高ARR的诊断效力.

  18. The pharmacological properties of lipophilic calcium antagonists.

    Science.gov (United States)

    van Zwieten, P A

    1998-01-01

    Several types of calcium antagonists (CA) (verapamil, diltiazem, nifedipine and related drugs) may be used as antihypertensives. In practice, the dihydropyridines (nifedipine and related drugs) are the CA used most frequently as antihypertensives. Apart from the lowering of blood pressure CA may lead to other, theoretically beneficial, effects: regression of left ventricular and vascular hypertrophy, renal protection, weak natriuretic, weak antiplatelet, anti-ischaemic and antiatherogenic activity. Several new dihydropyridine CA have been introduced in recent years. The advantages of the newer compounds, such as amlodipine, felodipine, isradipine, lacidipine and lercanidipine, may include: vasoselectivity, hence little or no cardiodepressant activity; an improved kinetic profile, resulting in a slow onset and long duration of action, fewer side-effects such as reflex tachycardia and headache, owing to the slow onset of the antihypertensive action. For a few newer CA a predominant effect on specialized circulatory beds (renal, coronary and cerebral) has been claimed. The new CA, which are clearly lipophilic, deserve special attention. Owing to the lipophilic character of such compounds considerable concentration occurs in lipid-containing membrane depots. The CA thus concentrated are slowly released from these depots and, subsequently, reach their targets, the L-type calcium channels. This phenomenon explains both the slow onset and the long duration of action of these CA. Owing to the slow onset of action reflex tachycardia is virtually absent. The long duration of action allows satisfactory control of blood pressure in hypertensives by means of a single daily dose. A few lipophilic dihydropyridine CA are vasoselective. This property implies that at therapeutic, vasodilatory dosages no cardiodepressant activity occurs. Lercanidipine is a recently introduced example of a lipophilic and vasoselective dihydropyridine CA. It is an effective vasodilator

  19. Application of SUSPPUP ratio in patients with primary aldosteronism%SUSPPUP指数在原发性醛固酮增多症诊断中的价值

    Institute of Scientific and Technical Information of China (English)

    孔剑琼; 李南方; 祖菲亚; 张德莲; 常桂娟

    2014-01-01

    目的 评估SUSPPUP指数(血钠与尿钠的比值除以血钾平方与尿钾的比值)在原发性醛固酮增多症(PA)筛查中的作用.方法 对952例高血压患者进行坐位血浆肾素活性(PRA)及醛固酮浓度(PAC)的检测,根据PA初筛标准及盐水负荷试验标准,筛查出PA组204例和排除PA的原发性高血压组261例,比较两组尿钾/尿钠、SUSPPUP指数和PAC/PRA比值(ARR)等指标的差异.构建和比较尿钾/尿钠、SUSPPUP指数和ARR对诊断PA的ROC曲线.结果 SUSPPUP曲线下面积0.797,与ARR曲线下面积相当(0.796).SUSPPUP的最佳切点为1.0,敏感性和特异性分别达到98.9%和81%.结论 SUSPPUP可以作为快速筛查PA一个价格不高的指标.%Objective To assess the effectiveness of the quotient of serum sodium to urinary sodium divided by (serum potassium) 2 to urinary potassium (SUSPPUP) in screening for primary aldosteronism (PA).Methods Among 952 patients with hypertension who had renin activity,aldosterone measurements and concomitant serum and urinary biochemistry data,204 patients were diagnosed as cases of PA and 261 as cases of essential hypertension.Diagnosis of PA was made in accordance with established laboratory criteria including renin activity and aldosterone,plasma aldosterone concentration/plasma renin activity (ARR),and saline loading test.The SUSPPUP ratio with the ARR were compared in two groups.Results The area under the curve of SUSPPUP and ARR was 0.797 and 0.796 respectively according to receiver operating characteristic curve,optimal cutoff of SUSPPUP was 1.0,the sensitivity and specificity of SUSPPUP was 98.9% and 81% respectively.Conclusions The SUSPPUP ratio is an inexpensive and rapid tool to assess the extent of mineralocorticoid excess,therefore,SUSPPUP ratio can be applied to screen PA in hypertensive patients.

  20. 330例原发性醛固酮增多症患者的临床分析%Clinical analysis of 330 patients with primry aldosteronism

    Institute of Scientific and Technical Information of China (English)

    李南方; 骆琴; 王梦卉; 胡君丽; 王磊; 李红建; 王红梅; 王新玲; 祖菲亚; 张德莲; 常桂娟; 努尔古丽; 周克明

    2011-01-01

    回顾性分析330例确诊原发性醛固酮增多症(PA)患者的临床资料。结果显示,330例PA患者均有高血压,其中3.64%的患者为1级高血压,20.91%为2级,75.45%为3级;PA患者青中年的比例为89.09%,超重肥胖者的比例为81.82%,与正常体重的PA患者相比,超重肥胖者中男性明显多于女性(P<0.01);低钾血症发生率32.12%,偏相关分析显示血钾水平与病程无相关。logistic回归分析显示醛固酮水平是PA患者发生低血钾的独立危险因素(P<0.01)。79.09%的患者血浆醛固酮水平>12 ng/dl且肾素活性<1 ng·ml-1 h-1,而94.24%的患者醛固酮肾素活性比值>20。%The clinical data of 330 patients with primary aldosteronism (PA) from January 2006 to March 2010 were retrospectively analyzed. The prevalence of 1, 2, and 3 stage hypertension in these subjects was 3.64%,20. 91%, and 75.45 %, respectively. Of all PA patients, 89.09% were young adults and 81.82% were overweight or obese. There was a marked preponderance of male patients in the overweight or obese group ( P<0. 01 ). The incidence of hypokalemia was 32. 12%. The concentration of serum potassium was not associated with the disease course. Logistic regression showed that the concentration of plasma aldosterone was an independent risk factor of hypokalemia in PA patients( P<0. 01 ). 79. 09% PA patients presented the plasma aldosterone level over 12 ng/dl and the renin activity level of less than 1 ng · ml-1 · h-1. The aldosterone-to-rennin activity ratio was >20 in 94.24% of the patients with PA.

  1. Clinical analysis of 31 cases of primary aldosteronism%原发性醛固酮增多症31例临床分析

    Institute of Scientific and Technical Information of China (English)

    蒋远斌; 苟欣

    2010-01-01

    目的 探讨原发性醛固酮增多症(primary adosteronism,PA)的特点、诊断及治疗要点,以提高诊治水平.方法 对我院31例术后病理确诊PA的临床资料进行总结,并结合文献分析.结果 31例均行手术治疗,其中肾上腺腺瘤28例,肾上腺皮质增生3例;以高血压为首发症状最多,低血钾表现次之;血浆醛固酮浓度/血浆肾素活性均>25/1;29例行后腹腔镜手术切除病灶及肾上腺组织,2例因自体瘤大行开放手术.结论 PA病程长,早期无特异临床症状,易误诊.ARR试验筛查可早期发现PA,CT扫描在定位及定性方面均优于B超,后腹腔镜手术是有效治疗手段,治疗效果良好.%Objective To approach the characteristics, diagnosis and treatment of primary aldosteronism for improving the level of diagnosis and treatment. Methods The data of 31 cases of pathologically confirmed primary aldosteronism seen from 2005 to 2009 were collected and analysed with literature. Results 31 patients included 28 cases of aldosterone-producing adenoma,3 cases of adrenocortical hyperplasia. Most patients had high blood pressure as the first symptom, followed by the manifestation of hypokalemia. Plasma aldosterone concentration/plasma renin activity was>25/1; in all patients 29 cases underwent laparoscopic surgery to remove lesions or adrenal tissue and 2 cases had open surgery because of the size of tumor. Conclusions This disease has a long course with non-specific clinical symptoms at the early stage, and easily be misdiagnosed. ARR screening test could detect PA early. CT scan is better than B-mode ultrasonography in both lesion location and qualitation. Retroperitoneal laparoscopic surgery is an effective treatment with satisfactory therapeutic outcome.

  2. Central role for sodium in the pathogenesis of blood pressure changes independent of angiotensin, aldosterone and catecholamines in type 1 (insulin-dependent) diabetes mellitus

    DEFF Research Database (Denmark)

    Feldt-Rasmussen, B; Mathiesen, E R; Deckert, T

    1987-01-01

    We studied 73 Type 1 (insulin-dependent) diabetic patients, 18 to 50 years of age, with a diabetes duration of more than five years. Group 1: normal urinary albumin excretion below 30 mg per 24 h (n = 19); group 2: microalbuminuria, 30-300 mg per 24 h (n = 36); and group 3: diabetic nephropathy, ...... = -0.24, p less than 0.05), and exchangeable sodium and aldosterone (n = 66, r = -0.36, p less than 0.002) in all patients. The catecholamine levels were also suppressed or normal in the patients.(ABSTRACT TRUNCATED AT 250 WORDS)...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    during low-salt diet in PE patients (n = 7), healthy pregnant women (n = 15), and nonpregnant women (n = 13). High-salt intake decreased renin and angiotensin II concentrations significantly in healthy pregnant women (P ... in aldosterone and increases in brain natriuretic peptid (BNP) were similar in the groups. In PE patients, uterine and umbilical artery indices were not adversely changed during low-salt diet. Creatinine clearance was significantly lower in PE with no change by salt intake. PE patients displayed alterations...

  4. Structure-based drug design identifies novel LPA3 antagonists.

    Science.gov (United States)

    Fells, James I; Tsukahara, Ryoko; Liu, Jianxiong; Tigyi, Gabor; Parrill, Abby L

    2009-11-01

    Compound 5 ([5-(3-nitrophenoxy)-1,3-dioxo-1,3-dihydro-2-isoindol-2-yl]acetic acid) was identified as a weak selective LPA(3) antagonist (IC(50)=4504 nM) in a virtual screening effort to optimize a dual LPA(2 and 3) antagonist. Structure-based drug design techniques were used to prioritize similarity search matches of compound 5. This strategy rapidly identified 10 novel antagonists. The two most efficacious compounds identified inhibit activation of the LPA(3) receptor by 200 nM LPA with IC(50) values of 752 nM and 2992 nM. These compounds additionally define changes to our previously reported pharmacophore that will improve its ability to identify more potent and selective LPA(3) receptor antagonists. The results of the combined computational and experimental screening are reported.

  5. Secondary prevention with calcium antagonists after acute myocardial infarction

    DEFF Research Database (Denmark)

    Hansen, J F

    1992-01-01

    Experimental studies have demonstrated that the 3 calcium antagonists nifedipine, diltiazem, and verapamil have a comparable effect in the prevention of myocardial damage during ischaemia. Secondary prevention trials after acute myocardial infarction, which aimed at improving survival...

  6. Perampanel: A Selective AMPA Antagonist for Treating Seizures

    OpenAIRE

    Krauss, Gregory L.

    2013-01-01

    Perampanel is a selective, noncompetitive AMPA receptor antagonist that has recently been approved for treating localization-related epilepsy. This article reviews the pharmacology, clinical development, efficacy, and safety/tolerability of perampanel.

  7. Complications of TNF-α antagonists and iron homeostasis

    Science.gov (United States)

    TNF-α is a central regulator of inflammation and its blockade downregulates other proinflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficia...

  8. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor...... antagonists as adjuvant single drugs to reduce trauma-, blood transfusion- and sepsis-induced immunosuppression has led to research in combined treatment regimens in major surgery, particularly, of patients operated on for malignant diseases....

  9. Structure-activity relationships of benzothiazole GPR35 antagonists.

    Science.gov (United States)

    Abdalhameed, Manahil M; Zhao, Pingwei; Hurst, Dow P; Reggio, Patricia H; Abood, Mary E; Croatt, Mitchell P

    2017-02-01

    The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound.

  10. Deficiency of interleukin-1 receptor antagonist responsive to anakinra.

    Science.gov (United States)

    Schnellbacher, Charlotte; Ciocca, Giovanna; Menendez, Roxanna; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Duarte, Ana M; Rivas-Chacon, Rafael

    2013-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acute-phase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy.

  11. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    OpenAIRE

    Mohammad eKhanfar; Anna eAffini; Kiril eLutsenko; Katarina eNikolic; Stefania eButini; Holger eStark

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex...

  12. Interleukin-2 receptor antagonists as induction therapy after heart transplantation

    DEFF Research Database (Denmark)

    Møller, Christian H; Gustafsson, Finn; Gluud, Christian;

    2008-01-01

    About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras.......About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras....

  13. Fibulin-5 expression in the aortas of model rats with aldosterone-producing adenomas%Fibulin-5在醛固酮腺瘤模型大鼠主动脉中的表达

    Institute of Scientific and Technical Information of China (English)

    闫永吉; 王超; 陈戬; 刘建和; 张劲松; 姜永明; 王光; 张海燕

    2011-01-01

    目的 观察醛固酮对主动脉Fibulin-5表达的影响.方法 将32只SD大鼠随机分为4组,每组8只:(1)空白溶剂设为对照(60%丙二醇+10%乙醇+30%双蒸水);(2)醛固酮腺瘤:泵入醛固酮(1 μg/h);(3)醛固酮腺瘤+特异性盐皮质激素受体阻断剂:依普利酮[100 mg/(kg·d)];(4)醛固酮腺瘤+血管扩张剂:肼苯哒嗪[25 mg/(kg·d)].渗透泵内分别注入醛固酮或空白溶剂,然后将其埋植于大鼠背部皮下.8周后,免疫组织化学和免疫印迹法检测主动脉Fibulin-5的表达.结果 与对照组大鼠比较,腺瘤组大鼠主动脉Fibulin-5的表达显著增加(P<0.05);与肼苯哒嗪不同,依普利酮可以抑制醛固酮的上述作用(P<0.05).结论 醛固酮可以直接诱导主动脉Fibulin-5 表达增加,后者在醛固酮增多引起的主动脉重构过程中可能发挥重要作用.%Objective To observe the effect of aldosterone on fibulin-5 expression in the aorta.Methods Thirty-two male rats were randomly divided into 4 groups;vehicle (control) ,aldosterone-producing adenoma, aldosterone-producing adenoma plus eplerenone or hydralazine. They were then implanted with an osmotic mini-pump that infused either aldosterone or the vehicle. After 8 weeks, Fibulin-5 was examined by immnuohistochemistry and Western blotting. Results Compared with controls, the model rats with aldosterone-producing ademoma exhibited elevated aortic expression of Fibulin-5. This effect of aldosterone was significantly suppressed after co-treatment with eplerenone but not with hydralazine. Conclusion It suggest that aldosterone directly promotes aortic expression of Fibulin-5 that may play an important role in aldosterone-induced aortic remodeling.

  14. Bcl-2 Expression in the Aortas of Model Rats with Aldosterone-Producing Adenomas%Bcl-2在醛固酮腺瘤模型大鼠主动脉中的表达

    Institute of Scientific and Technical Information of China (English)

    闫永吉; 陈戬; 刘建和; 张劲松; 姜永明; 王光; 张海燕

    2011-01-01

    目的:观察醛固酮对主动脉Bcl-2表达的影响.方法:32只SD大鼠随机均分为4组:①空白溶剂设为对照(60%丙二醇+10%乙醇+30%双蒸水);②醛固酮腺瘤:泵入醛固酮(1μg/h);③醛固酮腺瘤+依普利酮组:依普利酮(100 mg·kg-1·d-1);④醛固酮腺瘤+肼苯哒嗪组:肼苯哒嗪(25 mg·kg-1·d-1).渗透泵内分别注入醛固酮或空白溶剂,然后将其埋植于大鼠背部皮下.8周后,免疫组织化学和免疫印迹检测主动脉Bcl-2的表达.结果:与对照组相比,腺瘤组大鼠主动脉Bcl-2表达显著减少(P<0.05);依普利酮能够拮抗醛固酮对Bcl-2表达的抑制作用(P<0.05).结论:醛固酮通过抑制Bcl-2表达,调节细胞凋亡状态,可能是醛固酮诱导主动脉重构的机制之一.%Objective: To observe the effect of aldosterone on Bcl-2 expression in the aorta. Methods: Thirtytwo male rats were randomly divided into 4 groups; vehicle (control), aldosterone-producing adenoma, aldosterone-producing adenoma plus eplerenone or hydralazine. They were then implanted with an osmotic mini-pump that infused either aldosterone or the vehicle. After 8 weeks, Bcl-2 was examined by immunohistochemistry and Western blotting. Results:Compared with controls, the model rats with aldosterone-producing adenoma exhibited decreased aortic expression of Bcl-2. This effect of aldosterone was significantly reversed after co-treatment with eplerenone but not with hydralazine. Conclusions:This study's findings suggest that aldosterone directly suppresses aortic expression of Bcl-2 that may play an important role in aldosterone-induced aortic remodeling.

  15. 尿醛固酮在原发性醛固酮增多症筛查中的价值及钠摄入对其筛查效率的影响%The role of urinary aldosterone in primary aldosteronism screening and the effect of sodium intake on the screening efficiency

    Institute of Scientific and Technical Information of China (English)

    鄞国书; 张少玲; 严励; 吴木潮; 黎锋; 徐明彤; 程桦

    2012-01-01

    Objective To investigate the role of urinary aldosterone in primary aldosteronism(PA) screening and evaluate the effect of sodium intake on the screening efficiency. Methods Two hundred and sixty-nine outpatients and inpatients with hypertension were recruited from endocrinology department of the Second Affiliated Hospital of Zhongshan University between September 2006 and July 2009, including 237 patients with essential hypertension (EH) (119 female, 118 male, mean age 47. 41 years old) and 32 patients with PA (20 female, 12 male, mean age 41.9 years old). Serum aldosterone concentration (SAC) and plasma renin activity (PRA) were detected after standing for 1 hour in all subjects. 24 hour urine was collected for the detection of urinary aldosterone, sodium and potassium. The receiver operating characteristic ROC) curve was used to assess the role of urinary aldosterone in PA screening. Sodium intake was evaluated according to the ratio of urinary sodium to urinary potassium (urinary Na+ /K+ }. The patients with EH were divided into two groups according to the median of urinary Na+/K+ : pa-tients with high urinary Na+/K+ (n=119) and with low urinary Na+/K+ (n=118). The ROC curves were constructed in these two groups respectively and the PA group served as the same positive patients. Results Using the ROC curve to assess the role of urinary aldosterone in PA screening, the area under the curve was 0. 824(95% CI 0. 773-0. 867, P<0. 01). Based on Youderis index, the optimal cut-off point of PA diagnosis by urinary aldosterone was 11.6 g/24 h, with the sensitivity and specificity 81. 2% {95% CI 63. 3% - 92. 7%) and 74.3%(95% CI 68. 2%-79. 7%) respectively. Urinary aldosterone was negatively correlated with urinary Na+ /K+ in the patients with EH (r= 0.174, P<0. 01). Compared with the low urinary Na+/K+ group, the level of urinary aldosterone,SAC and PR A were lower in the high urinary Na+ /K+ group.Conclusion Urinary aldosterone can be used in PA screening, and the cut

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

    Science.gov (United States)

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

    2016-03-01

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

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

    Science.gov (United States)

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

    2016-02-01

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

  18. A pharmacophore model for dopamine D4 receptor antagonists

    Science.gov (United States)

    Boström, Jonas; Gundertofte, Klaus; Liljefors, Tommy

    2000-11-01

    A pharmacophore model for dopamine D4 antagonists has been developed on the basis of a previously reported dopamine D2 model. By using exhaustive conformational analyses (MM3* force field and the GB/SA hydration model) and least-squares molecular superimposition studies, a set of eighteen structurally diverse high affinity D4 antagonists have successfully been accommodated in the D4 pharmacophore model. Enantioselectivities may be rationalized by conformational energies required for the enantiomers to adopt their proposed bioactive conformations. The pharmacophore models for antagonists at the D4 and D2 receptor subtypes have been compared in order to get insight into molecular properties of importance for D2/D4 receptor selectivity. It is concluded that the bioactive conformations of antagonists at the two receptor subtypes are essentially identical. Receptor essential volumes previously identified for the D2 receptor are shown to be present also in the D4 receptor. In addition, a novel receptor essential volume in the D4 receptor, not present in the D2 receptor, has been identified. This feature may be exploited for the design of D4 selective antagonists. However, it is concluded that the major determinant for D2/D4 selectivity is the nature of the interactions between the receptor and aromatic ring systems. The effects of the electronic properties of these ring systems on the affinities for the two receptor subtypes differ substantially.

  19. Comparison of the effects of laparoscopic surgery in treatment of aldosteronism caused by aldosterone adenoma and unilateral adrenal hyperplasia%醛固酮腺瘤和单侧肾上腺增生导致醛固酮增多症腹腔镜手术效果比较

    Institute of Scientific and Technical Information of China (English)

    朱平

    2016-01-01

    目的:观察醛固酮腺瘤和单侧肾上腺增生导致醛固酮增多症腹腔镜手术效果。方法:以我院2013年3月—2014年3月收治的50例醛固酮增多症患者为研究对象,醛固酮腺瘤组38例、单侧肾上腺增生组12例,均行腹膜后腹腔镜手术,肿瘤体积较大且与周围组织界限清晰者行肾上腺部分切除,其他患者行肾上腺全切。观察围术期指标及术后症状变化,比较肾上腺部分切除与肾上腺全切手术情况。随访1年,比较疗效及复发情况。结果:肾上腺全切的醛固酮腺瘤手术时间显著高于肾上腺部分切除的醛固酮腺瘤及单侧肾上腺增生,差异有统计学意义(P<0.05),各组患者术中出血量、术后住院时间比较,差异无统计学意义(P>0.05)。2组患者术后1个月收缩压、舒张压、血浆醛固酮、醛固酮/肾素比值均显著降低,血钾、血浆肾素活性均显著升高,与术前比较差异有统计学意义(P<0.05)。患者术后1年均未见复发,单侧肾上腺增生、肾上腺全切醛固酮腺瘤、肾上腺部分切除醛固酮腺瘤治愈率分别为66.7%、64.7%、61.9%,组间比较差异无统计学意义(P<0.05)。结论:腹腔镜手术治疗醛固酮增多症两种亚型均有良好的疗效及安全性,对符合肾上腺部分切除指征患者,术中应尽可能保留患侧肾上腺组织。%Objective: To observe the effects of laparoscopic surgery in treatment of aldosteronism caused by aldosterone adenoma and unilateral adrenal hyperplasia.Methods: 50 cases of patients with aldosteronism treated in our hospital from March 2013 to March 2014 were chosen for this study, 12 cases included in unilateral adrenal hyperplasia group and 38 cases in aldosterone adenoma group, both groups underwent retroperitoneal laparoscopic surgery, the patients with larger tumor volume and well-circumscribed surrounding tissues underwent partial adrenalectomy

  20. 原发性醛固酮增多症中甲状旁腺素的变化及作用%Changes of parathyroid hormone in primary aldosteronism and its effects

    Institute of Scientific and Technical Information of China (English)

    张翠; 王卫庆

    2014-01-01

    Primary aldosteronism (PA) is a common form of secondary endocrine hypertension,which is characterized by hypertension,hypokelamia,myathenia,elevated serum aldosterone concentration and suppressed plasma renin activity.Besides,accumulating research evidences showed that parathyroid hormone (PTH) level was elevated in patients with primary aldosteronism,accompanied by secondary hyperparathyroidism.This review systemically introduces the interaction between aldosterone and PTH in PA patients.%原发性醛固酮增多症(原醛症)是最常见的内分泌性高血压,主要表现为高血压、低血钾、肌无力、血醛固酮水平升高及血浆肾素活性受抑制等.除以上生化特点,目前越来越多文章关注原醛症患者血甲状旁腺素水平升高,并伴继发性甲状旁腺功能亢进.本文就原醛症患者中醛固酮与甲状旁腺素相互作用及意义进行综述.

  1. Incidence and influencing factors of aldosterone breakthrough during therapy with angiotensin Ⅱ receptor bockers alone,or combined with angiotensin-converting enzyme inhibitors in patients with non-diabetic nephropathy

    Institute of Scientific and Technical Information of China (English)

    梁敏

    2013-01-01

    Objective To investigate the incidence and influen-cing factors of aldosterone breakthrough during therapy with angiotensin Ⅱ receptor blockers(ARB) alone,or combined with angiotensin-converting enzyme inhibitors(ACEI) in Chinese patients with non-diabetic

  2. The Apolipoprotein E Antagonistic Pleiotropy Hypothesis: Review and Recommendations

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Tuminello

    2011-01-01

    Full Text Available Research on apolipoprotein E (APOE has consistently revealed a relationship between the gene's ε4 allele and risk for development of Alzheimer's disease (AD. However, research with younger populations of ε4 carriers has suggested that the APOE ε4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area.

  3. Discovery of the improved antagonistic prolactin variants by library screening.

    Science.gov (United States)

    Liu, Yun; Gong, Wei; Breinholt, Jens; Nørskov-Lauritsen, Leif; Zhang, Jinchao; Ma, Qinhong; Chen, Jianhe; Panina, Svetlana; Guo, Wei; Li, Tengkun; Zhang, Jingyuan; Kong, Meng; Liu, Zibing; Mao, Jingjing; Christensen, Leif; Hu, Sean; Wang, Lingyun

    2011-11-01

    Prolactin (PRL), a potent growth stimulator of the mammary epithelium, has been suggested to be a factor contributing to the development and progression of breast and prostate cancer. Several PRL receptor (PRLR) antagonists have been identified in the past decades, but their in vivo growth inhibitory potency was restricted by low receptor affinity, rendering them pharmacologically unattractive for clinical treatment. Thus, higher receptor affinity is essential for the development of improved PRLR antagonistic variants with improved in vivo potency. In this study, we generated Site 1 focused protein libraries of human G129R-PRL mutants and screened for those with increased affinity to the human PRLR. By combining the mutations with enhanced affinities for PRLR, we identified a novel G129R-PRL variant with mutations at Site 1 that render nearly 50-fold increase in the antagonistic potency in vitro.

  4. ANTAGONISTIC BACTERIA AGAINST SCHIZOPHYLLUM COMMUNE FR. IN PENINSULAR MALAYSIA

    Directory of Open Access Journals (Sweden)

    ANTARJO DIKIN

    2006-01-01

    Full Text Available Schizophyllum commune Fr., is one of the important fungi, causes brown germ and seed rot of oil palm. Biodiversity of antagonistic bacteria from oil palm plantations in Peninsular Malaysia is expected to support in development of biopesticide. Isolation with liquid assay and screening antagonistic bacteria using dual culture assay were carried out in the bioexploration. A total of 265 bacterial isolates from plant parts of oil palm screened 52 antagonistic bacterial isolates against 5. commune. Bacterial isolates were identified by using Biolog* Identification System i.e. Bacillus macroccanus, B. thermoglucosidasius, Burkholderia cepacia, B. gladioli, B. multivorans, B pyrrocinia, B. spinosa, Corynebacterium agropyri, C. misitidis, Enterobacter aerogenes, Microbacterium testaceum, Pseudomonas aeruginosa, P. citronellolis, Rhodococcus rhodochrous, Serratia ficaria, Serratia sp., S. marcescens, Staphylococcus sciuri, Sternotrophomonas maltophilia.

  5. Neuroprotective Effects of Glutamate Antagonists and Extracellular Acidity

    Science.gov (United States)

    Kaku, David A.; Giffard, Rona G.; Choi, Dennis W.

    1993-06-01

    Glutamate antagonists protect neurons from hypoxic injury both in vivo and in vitro, but in vitro studies have not been done under the acidic conditions typical of hypoxia-ischemia in vivo. Consistent with glutamate receptor antagonism, extracellular acidity reduced neuronal death in murine cortical cultures that were deprived of oxygen and glucose. Under these acid conditions, N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isox-azolepropionate-kainate antagonists further reduced neuronal death, such that some neurons tolerated prolonged oxygen and glucose deprivation almost as well as did astrocytes. Neuroprotection induced by this combination exceeded that induced by glutamate antagonists alone, suggesting that extracellular acidity has beneficial effects beyond the attenuation of ionotropic glutamate receptor activation.

  6. First Irish birth following IVF therapy using antagonist protocol.

    LENUS (Irish Health Repository)

    Mocanu, E V

    2012-02-01

    BACKGROUND: During in vitro fertilization (IVF), the prevention of a premature LH surge was traditionally achieved using a gonadotrophin releasing hormone agonist (GnRH-a), and more recently, a GnRH antagonist. AIMS: We report a case of a 37 year old treated using the GnRH antagonist in a second completed cycle of IVF. METHODS: IVF was performed for primary infertility of 5-year duration due to frozen pelvis secondary to endometriosis. RESULTS: Following controlled ovarian hyperstimulation, oocyte recovery and fertilization, cleavage and transfer of two zygotes, a pregnancy established. A twin gestation was diagnosed at 7-weeks scan and pregnancy ended with the delivery of twin girls by emergency caesarean section. CONCLUSION: This is a first report of a delivery following IVF using the antagonist protocol in Ireland. Such therapy is patient friendly and its use should be introduced on a larger scale in clinical practice.

  7. Development and characterization of high affinity leptins and leptin antagonists.

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-02-11

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.

  8. Development and Characterization of High Affinity Leptins and Leptin Antagonists*

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-01-01

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin. PMID:21119198

  9. Are we missing a mineralocorticoid in teleost fish? Effects of cortisol, deoxycorticosterone and aldosterone on osmoregulation, gill Na+,K+-ATPase activity and isoform mRNA levels in Atlantic salmon

    Science.gov (United States)

    McCormick, S.D.; Regish, A.; O'Dea, M. F.; Shrimpton, J.M.

    2008-01-01

    It has long been held that cortisol, acting through a single receptor, carries out both glucocorticoid and mineralocorticoid actions in teleost fish. The recent finding that fish express a gene with high sequence similarity to the mammalian mineralocorticoid receptor (MR) suggests the possibility that a hormone other than cortisol carries out some mineralocorticoid functions in fish. To test for this possibility, we examined the effect of in vivo cortisol, 11-deoxycorticosterone (DOC) and aldosterone on salinity tolerance, gill Na+,K+-ATPase (NKA) activity and mRNA levels of NKA α1a and α1b in Atlantic salmon. Cortisol treatment for 6–14 days resulted in increased, physiological levels of cortisol, increased gill NKA activity and improved salinity tolerance (lower plasma chloride after a 24 h seawater challenge), whereas DOC and aldosterone had no effect on either NKA activity or salinity tolerance. NKA α1a and α1b mRNA levels, which increase in response to fresh water and seawater acclimation, respectively, were both upregulated by cortisol, whereas DOC and aldosterone were without effect. Cortisol, DOC and aldosterone had no effect on gill glucocorticoid receptor GR1, GR2 and MR mRNA levels, although there was some indication of possible upregulation of GR1 by cortisol (p = 0.07). The putative GR blocker RU486 inhibited cortisol-induced increases in salinity tolerance, NKA activity and NKA α1a and α1b transcription, whereas the putative MR blocker spironolactone had no effect. The results provide support that cortisol, and not DOC or aldosterone, is involved in regulating the mineralocorticoid functions of ion uptake and salt secretion in teleost fish.

  10. Interleukin-1-receptor antagonist in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan

    2007-01-01

    BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell...... proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive...

  11. Barnidipine, a long-acting slow onset calcium antagonist.

    Science.gov (United States)

    Korstanje, C

    2000-11-01

    Barnidipine is a stereochemically pure dihydropyridine calcium antagonist with a high potency. The drug showed a slow onset and long-lasting vasorelaxating effect in vitro, and strong antihypertensive activity in hypertension models. Barnidipine was shown to have a high vasoselectivity and offered protection in cardiac and renal ischaemia models. The in vitro drug:drug interaction profile suggests a low potential for clinically relevant interactions with concomitant medication. It can be anticipated that barnidipine is an attractive calcium antagonist, offering good blood pressure control without compensatory baroreflex activity.

  12. Hyperglycemia of Diabetic Rats Decreased by a Glucagon Receptor Antagonist

    Science.gov (United States)

    Johnson, David G.; Ulichny Goebel, Camy; Hruby, Victor J.; Bregman, Marvin D.; Trivedi, Dev

    1982-02-01

    The glucagon analog [l-Nα-trinitrophenylhistidine, 12-homoarginine]-glucagon (THG) was examined for its ability to lower blood glucose concentrations in rats made diabetic with streptozotocin. In vitro, THG is a potent antagonist of glucagon activation of the hepatic adenylate cyclase assay system. Intravenous bolus injections of THG caused rapid decreases (20 to 35 percent) of short duration in blood glucose. Continuous infusion of low concentrations of the inhibitor led to larger sustained decreases in blood glucose (30 to 65 percent). These studies demonstrate that a glucagon receptor antagonist can substantially reduce blood glucose levels in diabetic animals without addition of exogenous insulin.

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

    Directory of Open Access Journals (Sweden)

    Khushwant S. Bhullar

    2014-05-01

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

  14. 肾上腺醛固酮腺瘤大鼠模型的建立%Establishment of a Rat Model of Aldosterone-Producing Adenoma

    Institute of Scientific and Technical Information of China (English)

    闫永吉; 陆义芹; 王保军; 史涛坪; 王光; 张海燕

    2012-01-01

    目的 构建肾上腺醛固酮腺瘤大鼠模型.方法 16只SD大鼠随机分对照组合醛固酮腺瘤组,在ALZET2004的微量渗透泵储药仓内分别注入醛固酮溶液或空白溶剂,然后将其埋于大鼠背部皮下.ALZET2004微量渗透泵可以持续灌注4周,为使醛固酮作用时间达到8周,4周后更换渗透泵1次,同时尾套法测量大鼠尾动脉收缩压;8周后,放免法检测血浆醛固酮浓度和肾素活性.结果 3周后,与对照大鼠相比,腺瘤组大鼠收缩压开始升高,第7周达到顶峰,之后维持在高水平;腺瘤组大鼠血浆醛固酮的浓度显著升高 (P<0.01),肾素活性被抑制 (P<0.01).结论 大鼠皮下埋植微量渗透泵灌注醛固酮,可以成功构建大鼠醛固酮腺瘤模型.%Objective To establish a rat model of aldosterone-producing adenoma (APA). Methods 16 Sprague- Dawley rats subcutaneously implanted with an osmotic mini- pump, were randomly divided into 2 groups: control group (vehicle) and APA (1 μg/h) group. Because the mini- pump (ALZET 2004) could continuously infuse test substance for 4 weeks, another minipump was replaced after the fourth week to make the duration of aldosterone infusion for 8 weeks. Systolic blood pressure (SBP) was measured weekly by the tail-cuff method. At the termination of the study, blood was collected for measurements of plasma renin activity (PRA) and aldosterone concontration (PAC) with radioimmunoassay kits. Results After 3 weeks, APA rats showed significantly and progressively increased SBP compared with controls (P<0.05) , and the SBP level reached peak on 7th week and remained high levels. PRA was substantially depressed and PAC was significantly raised in APA rats (P<0.01) . Conclusion By implanting osmotic minipumps subcutaneously, the rat models of APA can be successfully established, which provide a good platform for investigating the pathogenesis of APA.

  15. Relationship between primary aldosteronism and osteoporosis%原发性醛固酮增多症与骨质疏松症的相关性

    Institute of Scientific and Technical Information of China (English)

    樊长萍; 侯建明

    2016-01-01

    Secondary osteoporosis , which is mainly caused by diseases , drugs, organ transplantation and other reasons, is a metabolic bone disease characterized by low bone mass , micro-architectural deterioration in bone tissue , with a consequent increase in bone fragility and susceptibility to fracture .To search for the cause of osteoporosis is of great significance for the treatment of secondary osteoporosis .In clinical work , we found that the morbidity of low bone mass/osteoporosis even fragility fractures in primary aldosteronism patients was higher than that of the general population .In re-cent years , studies have shown that there is an abnormal of mineral metabolism , low bone mass/osteoporosis even fragili-ty fractures risk in primary aldosteronism and hyperaldosteronism animal models and patients .This review focuses on the mechanisms of primary aldosteronism impacting on osteoporosis , including secondary hyperparathyroidism , osteoporosis-related gene , mineralocorticoid receptor , oxidative stress , epithelia1 sodium channel , and explores the relationship be-tween primary aldosteronism and osteoporosis , in order to provide evidence and method for the prevention and treatment of secondary osteoporosis .%继发性骨质疏松症是由于疾病、药物、器官移植等原因所致的骨量低下,骨微结构损坏,骨脆性增加和易发生骨折的代谢性骨病。积极寻找骨质疏松症的病因,对有效治疗继发性骨质疏松症具有重要意义。在临床工作中,笔者发现,原发性醛固酮增多症患者骨量减少/骨质疏松症甚至脆性骨折的发生率高于普通人群。近年来,研究显示,原发性醛固酮增多症及高醛固酮血症动物模型及患者体内普遍存在矿物质代谢异常,骨量减少/骨质疏松症甚至脆性骨折风险。本文从继发性甲状旁腺功能亢进症、骨质疏松症相关基因、盐皮质激素受体、氧化应激、上皮钠离子通道方面对原

  16. 5-Hydroxytryptamine3 receptor antagonists and cardiac side effects

    DEFF Research Database (Denmark)

    Brygger, Louise; Herrstedt, Jørn

    2014-01-01

    INTRODUCTION: 5-Hydroxytryptamine3-receptor antagonists (5-HT3-RA) are the most widely used antiemetics in oncology, and although tolerability is high, QTC prolongation has been observed in some patients. AREAS COVERED: The purpose of this article is to outline the risk of cardiac adverse events...

  17. The Effect of Antagonist Muscle Sensory Input on Force Regulation.

    Directory of Open Access Journals (Sweden)

    Tanya Onushko

    Full Text Available The purpose of this study was to understand how stretch-related sensory feedback from an antagonist muscle affects agonist muscle output at different contraction levels in healthy adults. Ten young (25.3 ± 2.4 years, healthy subjects performed constant isometric knee flexion contractions (agonist at 6 torque levels: 5%, 10%, 15%, 20%, 30%, and 40% of their maximal voluntary contraction. For half of the trials, subjects received patellar tendon taps (antagonist sensory feedback during the contraction. We compared error in targeted knee flexion torque and hamstring muscle activity, with and without patellar tendon tapping, across the 6 torque levels. At lower torque levels (5%, 10%, and 15%, subjects produced greater knee torque error following tendon tapping compared with the same torque levels without tendon tapping. In contrast, we did not find any difference in torque output at higher target levels (20%, 30%, and 40% between trials with and without tendon tapping. We also observed a load-dependent increase in the magnitude of agonist muscle activity after tendon taps, with no associated load-dependent increase in agonist and antagonist co-activation, or reflex inhibition from the antagonist tapping. The findings suggest that at relatively low muscle activity there is a deficiency in the ability to correct motor output after sensory disturbances, and cortical centers (versus sub-cortical are likely involved.

  18. Voltage-Gated Calcium Channel Antagonists and Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Bruce Lyeth

    2013-06-01

    Full Text Available Traumatic brain injury (TBI is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this review provide support for further development of voltage gated calcium channel (VGCC antagonists as potential therapeutic agents. Following TBI, neurons and astrocytes experience a rapid and sometimes enduring increase in intracellular calcium ([Ca2+]i. These fluxes in [Ca2+]i drive not only apoptotic and necrotic cell death, but also can lead to long-term cell dysfunction in surviving cells. In a limited number of in vitro experiments, both L-type and N-type VGCC antagonists successfully reduced calcium loads as well as neuronal and astrocytic cell death following mechanical injury. In rodent models of TBI, administration of VGCC antagonists reduced cell death and improved cognitive function. It is clear that there is a critical need to find effective therapeutics and rational drug delivery strategies for the management and treatment of TBI, and we believe that further investigation of VGCC antagonists should be pursued before ruling out the possibility of successful translation to the clinic.

  19. How Hybrid Organizations Turn Antagonistic Assets into Complementarities

    DEFF Research Database (Denmark)

    Hockerts, Kai

    2015-01-01

    This article focuses on people excluded from traditional markets as employees, producers, or consumers on the grounds that they lack the appropriate skills. It describes the processes through which these perceived liabilities can be overcome by so-called hybrid organizations. Hybrids pursue expli...... for complementarities, and by creating demands for antagonistic assets, or by using partnerships....

  20. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn;

    2011-01-01

    Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered: Preclin......Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered...... receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...... antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT2A receptor...

  1. Facilitative and antagonistic interactions between plant viruses in mixed infections.

    Science.gov (United States)

    Syller, Jerzy

    2012-02-01

    Mixed infections of plant viruses are common in nature, and a number of important virus diseases of plants are the outcomes of interactions between causative agents. Multiple infections lead to a variety of intrahost virus-virus interactions, many of which may result in the generation of variants showing novel genetic features, and thus change the genetic structure of the viral population. Hence, virus-virus interactions in plants may be of crucial significance for the understanding of viral pathogenesis and evolution, and consequently for the development of efficient and stable control strategies. The interactions between plant viruses in mixed infections are generally categorized as synergistic or antagonistic. Moreover, mixtures of synergistic and antagonistic interactions, creating usually unpredictable biological and epidemiological consequences, are likely to occur in plants. The mechanisms of some of these are still unknown. This review aims to bring together the current knowledge on the most commonly occurring facilitative and antagonistic interactions between related or unrelated viruses infecting the same host plant. The best characterized implications of these interactions for virus-vector-host relationships are included. The terms 'synergism' and 'helper dependence' for facilitative virus-virus interactions, and 'cross-protection' and 'mutual exclusion' for antagonistic interactions, are applied in this article.

  2. Determinants of effective, safe and convenient vitamin K antagonist use

    NARCIS (Netherlands)

    Kooistra, Hilde Afra Margaretha

    2016-01-01

    Vitamin K antagonists (VKA) are frequently used anticoagulants. They are very effective in preventing atrial fibrillation related strokes and recurrent venous thrombosis. However, it can be difficult to achieve an optimal balance between the efficacy and side effects (bleeding), as the dose response

  3. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  4. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

    NARCIS (Netherlands)

    Parry-Jones, A.R.; Napoli, M. Di; Goldstein, J.N.; Schreuder, F.H.; Tetri, S.; Tatlisumak, T.; Yan, B.; Nieuwenhuizen, K.M.; Dequatre-Ponchelle, N.; Lee-Archer, M.; Horstmann, S.; Wilson, D.; Pomero, F.; Masotti, L.; Lerpiniere, C.; Godoy, D.A.; Cohen, A.S.; Houben, R.; Al-Shahi Salman, R.; Pennati, P.; Fenoglio, L.; Werring, D.; Veltkamp, R.; Wood, E.; Dewey, H.M.; Cordonnier, C.; Klijn, C.J.M.; Meligeni, F.; Davis, S.M.; Huhtakangas, J.; Staals, J.; Rosand, J.; Meretoja, A.

    2015-01-01

    OBJECTIVE: There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different

  5. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

    NARCIS (Netherlands)

    Parry-Jones, Adrian R.; Di Napoli, Mario; Goldstein, Joshua N.; Schreuder, Floris H B M; Tetri, Sami; Tatlisumak, Turgut; Yan, Bernard; Van Nieuwenhuizen, Koen M.; Dequatre-Ponchelle, Nelly; Lee-Archer, Matthew; Horstmann, Solveig; Wilson, Duncan; Pomero, Fulvio; Masotti, Luca; Lerpiniere, Christine; Godoy, Daniel Agustin; Cohen, Abigail S.; Houben, Rik; Al-Shahi Salman, Rustam; Pennati, Paolo; Fenoglio, Luigi; Werring, David; Veltkamp, Roland; Wood, Edith; Dewey, Helen M.; Cordonnier, Charlotte; Klijn, Catharina J M; Meligeni, Fabrizio; Davis, Stephen M.; Huhtakangas, Juha; Staals, Julie; Rosand, Jonathan; Meretoja, Atte

    2015-01-01

    Objective There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different

  6. Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists.

    Science.gov (United States)

    Kim, Jeeyeon; Kim, Youngjae; Tae, Jinsung; Yeom, Miyoung; Moon, Bongjin; Huang, Xi-Ping; Roth, Bryan L; Lee, Kangho; Rhim, Hyewhon; Choo, Il Han; Chong, Youhoon; Keum, Gyochang; Nam, Ghilsoo; Choo, Hyunah

    2013-11-01

    The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7 R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7 R. Among the synthesized compounds, 1-([2'-methoxy-(1,1'-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7 R (pKi =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7 R over other serotonin receptor subtypes, such as 5-HT1 R, 5-HT2 R, 5-HT3 R, and 5-HT6 R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function.

  7. Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children

    DEFF Research Database (Denmark)

    Bisgaard, H; Nielsen, K G

    2000-01-01

    We hypothesized that a leukotriene receptor antagonist (LTRA) could provide bronchoprotection against the cold, dry air-induced response in asthmatic preschool children. In a randomized, double-blind, placebo-controlled crossover study, we examined the effect of the specific LTRA montelukast at 5...

  8. Does intergenerational social mobility affect antagonistic attitudes towards ethnic minorities?

    NARCIS (Netherlands)

    Tolsma, J.; Graaf, N.D. de; Quillian, L.

    2009-01-01

    Up till now, no study satisfactorily addressed the effect of social mobility on antagonistic attitudes toward ethnic minorities. In this contribution, we investigate the effect of educational and class intergenerational mobility on ethnic stereotypes, ethnic threat, and opposition to ethnic intermar

  9. Komplikationer til langtidsbehandling med vitamin K-antagonister

    DEFF Research Database (Denmark)

    May, O; Garne, E; Mickley, H

    1990-01-01

    Long-term treatment with vitamin K antagonists (vKA) frequently involves complications. The commonest complication is haemorrhage and cases of serious haemorrhage are stated in the literature to occur with a frequency per 1,000 treatment years of 12-108, of which 2-17 are fatal. The majority...

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2016-03-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2010-01-01

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

  13. Myofascial force transmission via extramuscular pathways occurs between antagonistic muscles.

    Science.gov (United States)

    Huijing, Peter A; Baan, Guus C

    2008-01-01

    Most often muscles (as organs) are viewed as independent actuators. To test if this is true for antagonistic muscles, force was measured simultaneously at: (1) the proximal and distal tendons of the extensor digitorum muscle (EDL) to quantify any proximo-distal force differences, as an indicator of myofascial force transmission, (2) at the distal tendons of the whole antagonistic peroneal muscle group (PER) to test if effects of EDL length changes are present and (3) at the proximal end of the tibia to test if myofascially transmitted force is exerted there. EDL length was manipulated either at the proximal or distal tendons. This way equal EDL lengths are attained at two different positions of the muscle with respect to the tibia and antagonistic muscles. Despite its relatively small size, lengthening of the EDL changed forces exerted on the tibia and forces exerted by its antagonistic muscle group. Apart from its extramuscular myofascial connections, EDL has no connections to either the tibia or these antagonistic muscles. Proximal EDL lengthening increased distal muscular forces (active PER DeltaF approximately +1.7%), but decreased tibial forces (passive from 0.3 to 0 N; active DeltaF approximately -5%). Therefore, it is concluded that these antagonistic muscles do not act independently, because of myofascial force transmission between them. Such a decrease in tibial force indicates release of pre-strained connections. Distal EDL lengthening had opposite effects (tripling passive force exerted on tibia; active PER force DeltaF approximately -3.6%). It is concluded that the length and relative position of the EDL is a co-determinant of passive and active force exerted at tendons of nearby antagonistic muscle groups. These results necessitate a new view of the locomotor apparatus, which needs to take into account the high interdependence of muscles and muscle fibres as force generators, as well as proximo-distal force differences and serial and parallel

  14. Relationship between adiponectin and cardiac damage induced by aldosterone in SD rats%脂联素与醛固酮介导的SD大鼠心脏损害的关系

    Institute of Scientific and Technical Information of China (English)

    王川; 严励; 张少玲; 程桦

    2010-01-01

    Objective To investigate relationship between adiponectin and cardiac damage induced by aldosterone in SD rats. Methods Male SD rats were treated with aldosterone infusion for 4 weeks, systolic blood pressure (SBP) was measured every week. At the end of experiment, the myocardial structure was observed, the levels of adiponectin in plasma and adiponectin mRNA expression of adipose tissue in epididymal fat pad were measured. 3T3-L1 adipocytes treated with 10-8 and 10-6 moL/L aldosterone for 24 and 48 h, adiponectin mRNA expressions and adiponectin concentrations in culture medium were measured. Results Aldosterone induced only a slight increase in the SBP of SD rats[(123±7)mm Hg, P<0.05]. However, aldosterone significantly induced cardiac ultrastructure changes, such as mitochondrial swelling and disordered internal structures. Furthermore, the level of plasma adiponectin decreased 22.8% after aldosterone treatment for 4 weeks ( P<0. 05 ). When 3T3-L1 adipocytes were treated with 10-8 and 10-6 mol/L aldosterone for 24 h, adiponectin concentrations in culture medium decreased 21.8% and 27. 2%, respectively (P < 0. 05); for 48 h, adiponctin mRNA expressions decreased 22.1% and 37.4%, respectively ( P<0. 05 ). The effect of aldosterone was reversed by spironolactone,which was partly independent of SBP. Conclusions Low level of adiponectin may be involved in cardiac damage induced by aldosterone in SD rats.%目的 探讨脂联素与醛固酮介导的SD大鼠心肌损害的关系.方法 雄性SD大鼠0.75μg/h皮下持续输注醛固酮4周,观察血压、心肌结构改变,测定血浆脂联素水平和附睾脂肪垫脂肪组织脂联素基因表达.体外培养3T3-L1脂肪细胞,10-8和10-6 mol/L醛固酮作用24和48 h,观察脂联素基因表达和培养液中脂联素浓度的变化.结果 醛固酮作用SD大鼠4周,血压轻微上升[(123±7)mm Hg,P<0.05],但心肌超微结构已有明显损伤如线粒体肿胀、内部结构不清等;同时,大鼠血浆脂

  15. 代谢综合征在原发性醛固酮增多症中的患病特征%The clinical characateristics of the metabolic syndrome in patients with primary aldosteronism

    Institute of Scientific and Technical Information of China (English)

    李东晓; 郭立新; 潘琦

    2011-01-01

    Objective To assess the characteristics of the metabolic syndrome (MS) in patients with primary aldosteronism by analyzing the clinical information of 62 patients with primary aldosteronism (PA) ,and to explore the possible mechanism of the effects of aldosterone on the metabolism. Methods We analysed all the 62 patients with PA,60 patients with essential hypertension ( EH ). Results 1. The prevalence of MS in PA group was higher than in EH group,distribution of single components of the meta bolic syndrome other than hypertension and obesity showed a higher prevalence of hyportriglycerids,lower ing high-density lipoprotein cholesterol(HDL-C) and hyperglycemia in PA than in EH. 2. The correlation study show that aldosterone was associated with BMI, plasma and uremia potassium. The aldosterone renin ratio was associated with TC and LDL-C. Conclusions 1. The primary aldosteronism was closely associat ed with metabolic syndrome, and the metabolic abnormalities including hyperglycemia and dyslipidemia was more common in patients with PA. 2. The effects of aldosterone on the metabolinism was associated with the activity of the rennin, and the aldosterone renin ratio was better than the plasma aldosterone level to reflect the effects on metabolism..%目的 通过分析62例原发性醛同酮增多症(原醛症)患者的临床资料,了解代谢综合征在原醛症患者中的发病及临床特征,并初步探讨醛固酮对代谢影响及可能的机制.方法 收集62例原醛症患者和60例年龄和体质指数相匹配的原发性高血压患者的临床资料.结果 1.原醛症患者中代谢综合征的患病率高于原发性高血压对照组,且在代谢综合征中除高血压和肥胖外、血脂异常和糖调节异常的患病率也高于对照组.2.相关分析显示卧位血浆醛固酮水平与体质指数、腰围、血钾及尿钾水平明显负相关,立位醛同酮水平与体质指数显著负相关,醛同酮/肾素比值与总胆同醇、低密度

  16. Accumulation of Deleterious Mutations Near Sexually Antagonistic Genes

    Directory of Open Access Journals (Sweden)

    Tim Connallon

    2016-08-01

    Full Text Available Mutation generates a steady supply of genetic variation that, while occasionally useful for adaptation, is more often deleterious for fitness. Recent research has emphasized that the fitness effects of mutations often differ between the sexes, leading to important evolutionary consequences for the maintenance of genetic variation and long-term population viability. Some forms of sex-specific selection—i.e., stronger purifying selection in males than females—can help purge a population’s load of female-harming mutations and promote population growth. Other scenarios—e.g., sexually antagonistic selection, in which mutations that harm females are beneficial for males—inflate genetic loads and potentially dampen population viability. Evolutionary processes of sexual antagonism and purifying selection are likely to impact the evolutionary dynamics of different loci within a genome, yet theory has mostly ignored the potential for interactions between such loci to jointly shape the evolutionary genetic basis of female and male fitness variation. Here, we show that sexually antagonistic selection at a locus tends to elevate the frequencies of deleterious alleles at tightly linked loci that evolve under purifying selection. Moreover, haplotypes that segregate for different sexually antagonistic alleles accumulate different types of deleterious mutations. Haplotypes that carry female-benefit sexually antagonistic alleles preferentially accumulate mutations that are primarily male harming, whereas male-benefit haplotypes accumulate mutations that are primarily female harming. The theory predicts that sexually antagonistic selection should shape the genomic organization of genetic variation that differentially impacts female and male fitness, and contribute to sexual dimorphism in the genetic basis of fitness variation.

  17. Ubiquitination profiling identifies sensitivity factors for IAP antagonist treatment.

    Science.gov (United States)

    Varfolomeev, Eugene; Izrael-Tomasevic, Anita; Yu, Kebing; Bustos, Daisy; Goncharov, Tatiana; Belmont, Lisa D; Masselot, Alexandre; Bakalarski, Corey E; Kirkpatrick, Donald S; Vucic, Domagoj

    2015-02-15

    Evasion of cell death is one crucial capability acquired by tumour cells to ward-off anti-tumour therapies and represents a fundamental challenge to sustaining clinical efficacy for currently available agents. Inhibitor of apoptosis (IAP) proteins use their ubiquitin E3 ligase activity to promote cancer cell survival by mediating proliferative signalling and blocking cell death in response to diverse stimuli. Using immunoaffinity enrichment and MS, ubiquitination sites on thousands of proteins were profiled upon initiation of cell death by IAP antagonists in IAP antagonist-sensitive and -resistant breast cancer cell lines. Our analyses identified hundreds of proteins with elevated levels of ubiquitin-remnant [K-GG (Lys-Gly-Gly)] peptides upon activation of cell death by the IAP antagonist BV6. The majority of these were observed in BV6-sensitive, but not-resistant, cells. Among these were known pro-apoptotic regulators, including CYC (cytochrome c), RIP1 (receptor-interacting protein 1) and a selection of proteins known to reside in the mitochondria or regulate NF-κB (nuclear factor κB) signalling. Analysis of early time-points revealed that IAP antagonist treatment stimulated rapid ubiquitination of NF-κB signalling proteins, including TRAF2 [TNF (tumour necrosis factor) receptor-associated factor 2], HOIL-1 (haem-oxidized iron-regulatory protein 2 ubiquitin ligase-1), NEMO (NF-κB essential modifier), as well as c-IAP1 (cellular IAP1) auto-ubiquitination. Knockdown of several NF-κB pathway members reduced BV6-induced cell death and TNF production in sensitive cell lines. Importantly, RIP1 was found to be constitutively ubiquitinated in sensitive breast-cancer cell lines at higher basal level than in resistant cell lines. Together, these data show the diverse and temporally defined roles of protein ubiquitination following IAP-antagonist treatment and provide critical insights into predictive diagnostics that may enhance clinical efficacy.

  18. 醛固酮合酶基因和11-β羟化酶基因多态性及其单体型与醛固酮瘤发病风险的关系%Association of aldosterone synthase and 11-beta hydroxylase genes polymorphism and haplotype with susceptibility of aldosterone producing adenoma

    Institute of Scientific and Technical Information of China (English)

    王保军; 陈路遥; 李新涛; 马鑫; 杨素霞; 欧阳金芝; 张旭

    2014-01-01

    目的 探讨醛固酮合酶基因(CYP11B2)和11-β羟化酶基因(CYP11B1)多态性及其单体型与醛固酮瘤发病风险的关系.方法 提取81例醛固酮瘤患者和103例对照人群外周血DNA,应用2个独立聚合酶链反应(PCR)和TaqMan探针技术对CYP11B2和CYP11B1基因的7个多态性位点(rs6387、rs6410、rs3097、rs4539、intron2转位、rs1799998、rs 13268025)进行基因分型,采用Logistic回归模型分析不同等位基因、基因型和单体型与醛固酮瘤发病风险的相关性.结果 intron2转位多态性位点C等位基因在病例组中的分布频率(25.3%)高于对照组(15.0%),携带C等位基因的个体较携带W等位基因的个体发生醛固酮瘤的风险增加了1.04倍(P<0.01).rs13268025位点中携带C等位基因的个体较携带T等位基因的个体发生醛固酮瘤的风险增加了0.91倍(P<0.05).7个多态性位点间存在着不同程度的连锁不平衡.单体型分析示AGGAWTT为最常见的单体型,单体型GAGAWTT是AGGAWTT发病风险的4.43倍(P<0.01).结论 CYP11B2和CYP11B1基因多态性与醛固酮瘤发病风险明显相关,intron2转位多态性位点的C等位基因、rs13268025位点的C等位基因、单体型GAGAWTT是醛固酮瘤发病的危险因素.%Objective To evaluate the effects of aldosterone synthase (CYP1 1B2) and 11-beta hydroxylase (CYP1 1 B1) genes polymorphism and haplotype on the susceptibility of aldosterone producing adenoma.Methods Peripheral blood DNA was extracted from 81 aldosterone producing adenoma patients and 103 control subjects.Real-time TaqMan probes technique and two seperate PCRs were used for genotyping seven polymorphism sites of the CYP1 1B2 and CYP11B1 genes (rs6387,rs6410,rs3097,rs4539,intron 2 conversion,rs1799998,rs13268025).Logistic regression model was performed to analyze the relationship of different genotypes or haplotype and the susceptibility of aldosterone producing adenoma.Results The frequency for allele C at site intron 2

  19. Design, synthesis, and structure-activity relationship of novel CCR2 antagonists.

    Science.gov (United States)

    Kothandaraman, Shankaran; Donnely, Karla L; Butora, Gabor; Jiao, Richard; Pasternak, Alexander; Morriello, Gregori J; Goble, Stephen D; Zhou, Changyou; Mills, Sander G; Maccoss, Malcolm; Vicario, Pasquale P; Ayala, Julia M; Demartino, Julie A; Struthers, Mary; Cascieri, Margaret A; Yang, Lihu

    2009-03-15

    A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.

  20. Design and discovery of 1,3-benzodiazepines as novel dopamine antagonists.

    Science.gov (United States)

    Zhu, Zhaoning; Sun, Zhong-Yue; Ye, Yuanzan; McKittrick, Brian; Greenlee, William; Czarniecki, Michael; Fawzi, Ahmad; Zhang, Hongtao; Lachowicz, Jean E

    2009-09-01

    A series of novel 1,3-benzodiazapine based D1 antagonists was designed according to the understanding of pharmacophore models derived from SCH 23390 (1b), a potent and selective D1 antagonist. The new design features an achiral cyclic-amidine that maintains desired basicity. Solid phase synthesis was developed for SAR development of the novel dopamine antagonists.

  1. Lead optimization studies of cinnamic amide EP2 antagonists.

    Science.gov (United States)

    Ganesh, Thota; Jiang, Jianxiong; Yang, Myung-Soon; Dingledine, Ray

    2014-05-22

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role.

  2. Anti-antimicrobial peptides: folding-mediated host defense antagonists.

    Science.gov (United States)

    Ryan, Lloyd; Lamarre, Baptiste; Diu, Ting; Ravi, Jascindra; Judge, Peter J; Temple, Adam; Carr, Matthew; Cerasoli, Eleonora; Su, Bo; Jenkinson, Howard F; Martyna, Glenn; Crain, Jason; Watts, Anthony; Ryadnov, Maxim G

    2013-07-12

    Antimicrobial or host defense peptides are innate immune regulators found in all multicellular organisms. Many of them fold into membrane-bound α-helices and function by causing cell wall disruption in microorganisms. Herein we probe the possibility and functional implications of antimicrobial antagonism mediated by complementary coiled-coil interactions between antimicrobial peptides and de novo designed antagonists: anti-antimicrobial peptides. Using sequences from native helical families such as cathelicidins, cecropins, and magainins we demonstrate that designed antagonists can co-fold with antimicrobial peptides into functionally inert helical oligomers. The properties and function of the resulting assemblies were studied in solution, membrane environments, and in bacterial culture by a combination of chiroptical and solid-state NMR spectroscopies, microscopy, bioassays, and molecular dynamics simulations. The findings offer a molecular rationale for anti-antimicrobial responses with potential implications for antimicrobial resistance.

  3. Churg-Strauss syndrome associated with leukotriene receptor antagonists (LTRA).

    Science.gov (United States)

    Cuchacovich, R; Justiniano, M; Espinoza, L R

    2007-10-01

    Churg-Strauss syndrome (CSS) is a rare vasculitic disorder that generally occurs in patients with bronchial asthma. CSS is being increasingly recognized in asthmatic patients treated with leukotriene receptor antagonists. However, the nature of this relationship remains to be elucidated. The present report describes three asthmatic patients who developed clinical manifestations highly suggestive of CSS, although one patient lacked the presence of eosinophilia. The patient, however, exhibited biopsy-proven cutaneous necrotizing vasculitis, which improved after withdrawal of montelukast. The second patient presented with systemic constitutional signs including fever, malaise, arthralgias, clinical jaundice, peripheral blood eosinophilia, and biopsy-proven eosinophilic hepatitis. The third patient also had circulating eosinophilia, scleritis, and arthritis. All patients improved after discontinuation of the leukotriene receptor antagonist (montelukast).

  4. Potential Clinical Implications of the Urotensin II Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Emilie Kane

    2011-07-01

    Full Text Available Urotensin-II (UII, which binds to its receptor UT, plays an important role in the heart, kidneys, pancreas, adrenal gland and CNS. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, this constriction-dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in ACAT-1 activity leading to SMC proliferation and foam cell infiltration, insulin resistance (DMII, as well as inflammation, high blood pressure and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino-isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases.

  5. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    Considerable evidence has emerged to suggest that histamine participates in the regulation of the inflammatory response, immune reaction, coagulation cascade, and cardiovascular function. Furthermore, histamine may play a major role in the growth of normal and malignant tissue as a regulator...... of proliferation and angiogenesis. Specific histamine receptors have been identified on the surface of bone marrow cells, immune competent cells, endothelial cells, fibroblasts, and also on malignant cells. This has prompted research in regulation by specific histamine receptor agonists and antagonists. Results...... from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor...

  6. Are peripheral opioid antagonists the solution to opioid side effects?

    LENUS (Irish Health Repository)

    Bates, John J

    2012-02-03

    Opioid medication is the mainstay of therapy for severe acute and chronic pain. Unfortunately, the side effects of these medications can affect patient comfort and safety, thus limiting their proven therapeutic potential. Whereas the main analgesic effects of opioids are centrally mediated, many of the common side effects are mediated via peripheral receptors. Novel peripheral opioid antagonists have been recently introduced that can block the peripheral actions of opioids without affecting centrally mediated analgesia. We review the clinical and experimental evidence of their efficacy in ameliorating opioid side effects and consider what further information might be useful in defining their role. IMPLICATIONS: The major analgesic effects of opioid medication are mediated within the brain and spinal cord. Many of the side effects of opioids are caused by activation of receptors outside these areas. Recently developed peripherally restricted opioid antagonists have the ability to block many opioid side effects without affecting analgesia.

  7. Non-imidazole histamine NO-donor H3-antagonists.

    Science.gov (United States)

    Tosco, Paolo; Bertinaria, Massimo; Di Stilo, Antonella; Cena, Clara; Fruttero, Roberta; Gasco, Alberto

    2005-01-01

    Recently a series of H3-antagonists related to Imoproxifan was realised (I); in these products the oxime substructure of the lead was constrained in NO-donor furoxan systems and in the corresponding furazan derivatives. In this paper, a new series of compounds derived from I by substituting the imidazole ring with the ethoxycarbonylpiperazino moiety present in the non-imidazole H3-ligand A-923 is described. For all the products synthesis and preliminary pharmacological characterisation, as well as their hydrophilic-lipophilic balance, are reported. The imidazole ring replacement generally results in a decreased H3-antagonist activity with respect to the analogues of series I and, in some cases, induces relaxing effects on the electrically contracted guinea-pig ileum, probably due to increased affinity for other receptor systems.

  8. Proteinuria in patients with primary aldosteronism%原发性醛固酮增多症患者蛋白尿情况分析

    Institute of Scientific and Technical Information of China (English)

    李南方; 马轩; 王红梅; 李娟; 王新国

    2013-01-01

    目的 调查原发性醛固酮增多症(PA)与原发性高血压(EH)患者蛋白尿检出率的差异,并分析PA患者蛋白尿可能的危险因素.方法 收集新疆维吾尔自治区人民医院高血压中心2006-01-2010-01因临床特征高度怀疑为PA,且排除睡眠呼吸暂停综合征、嗜铬细胞瘤等其他类型继发性高血压并行24 h尿蛋白定量检测的患者401例.患者均经坐位肾素活性及醛固酮测定并计算血浆醛固酮与肾素活性比值(ARR)初筛、盐水负荷试验或卡托普利试验这一诊断流程,最终确诊PA患者155例为PA组,排除PA患者246例为EH组.分析两组尿蛋白、蛋白尿检出率的差异,并采用多元线性回归模型分析PA患者蛋白尿可能的危险因素.结果 与EH患者相比,PA患者的24 h尿蛋白[(1.99±0.37)比(1.85±0.34)g/24 h,P<0.01]、蛋白尿的检出率(14.2%比6.5%,P=0.01)明显增高.进一步用Logistic模型校正年龄、性别及高血压病程后,PA患者蛋白尿检出率仍然高于高血压患者(P=0.031),且PA患者蛋白尿的风险增高(OR 2.152).在PA患者中,校正年龄、高血压病程、血压及血浆肾素活性后,血浆醛固酮是蛋白尿的危险因素(β=0.232,P=0.021).结论 PA患者尿蛋白及蛋白尿检出率较高,增高的醛固酮是其主要致病因素.%Objective To study the proteinuria detection rate in patients with primary aldosteronism (PA) and essential hypertension (EH) , and to explore the possible risk factors for proteinuria in patients with PA. Methods From the hypertension department of People's Hospital of Xinjiang Uygur Autonomous Region between January 2006 and January 2010, a total of 401 inpatients were selected, who were highly suspected of PA without sleep apnea syndrome, pheochromocytoma or any other secondary hypertension. All the subjects underwent 24-hour urinary protein quantitative detection, serum aldosterone concentration and plasma renin activity (PRA) detection at the sitting position

  9. Comparison glucolipid metabolism between primary aldosteronism and essential hypertension%原发性醛固酮增多症与原发性高血压的糖脂代谢比较

    Institute of Scientific and Technical Information of China (English)

    玛丽娅·木哈什; 龚艳春; 郭冀珍; 初少莉; 陈绍行; 高平进; 朱鼎良

    2012-01-01

    Objective : To compare the characteristics of glucolipid metabolism between patients with primary aldosteronism (PA) and those with essential hypertension (EH). Methods:We recruited 431 cases diagnosed as primary aldosteronism, 256 patients having adrenal venous sampling (AVS). According to the results of AVS, all subjects were divided into two groups: 147 patients with lateralized primary aldosteronism (LPA) and 109 patients with nonlateralized primary aldosteronism (NLPA). A total of 200 matched patients with essential hypertension were used as controls. The clinical data of patients in each group were collected, calculated for the prevalence of PA, and compared in the glucolipid metabolism characteristics. Results: (1) The prevalence of PA was 10.54% (431/4100) ; (2) Body mass index (BMI) and waistline in PA group was higher than those in EH group; (3) Triglycerides levels in LPA was higher than in NLPA and EH, and high-density lipoprotein in NLPA group was lower than in EH; (4) Post-prandial serum glucose and insulin levels, and insulin resistance index were higher in PA than in EH group, and those in NLPA was higher than in LPA group within PA groups (5) BMI can increase the risk of LPA group (OR = 2. 24, P = 0.024); (6) Triglycerides levels was significantly positively correlated with urine aldosterone, BMI was positively correlated with sitting aldosteronism levels, post-prandial serum insulin levels and insulin resistance index were significantly positively correlated with serum aldosterone and urine aldosterone levels. Conclusion: Abnormalities of glucolipid metabolism in PA group are severe (especially LPA was more severe than NLPA in lipid metabolism and NLPA was more severe compared with LPA in glucose metabolism) than those in EH group.%目的:比较原发性醛固酮增多症与原发性高血压的糖脂代谢特征. 方法:431例已确诊的原发性醛固酮增多症(PA)患者,其中256例行肾上腺静脉取血,分为原醛单侧组(LPA,n=147)

  10. 原发性醛固酮增多症临床诊疗分析(附63例报告)%Analysis of diagnosis and treatment of primary aldosteronism:(Report of 63 cases)

    Institute of Scientific and Technical Information of China (English)

    高兴成; 胡鹏; 茹伯战

    2012-01-01

    Objective: To study the diagnosis and treatment of primary-aldosteronism(PA). Methods: Clinical data of 63 patients diagnosed as primary aldosteronism were retrospectively analysed. Results: All patients appeared with arterial hypertension in different degree,58 cases were with hypokalemia, 19 patients were aldosteronism al-dosterone-producing adenoma and 14 patients were adrenal hyperplasia respectively by the determination of hormone levels that peripheral blood and adrenal venons blood. The 19 cases with aldosterom-producing adenoma underwent laparoscop adrenalectomy. The rest measured peripheral and adrenal venous sampling,and the results of 41 cases were that the adrenal vein aldosterone-cortisol ratio of the dominant side to the weaker side ratio> 2,and peripheral venous aldosterone levels above 0. 520 5 pmol/L,and plasma aldosterone to renin ratio ≥40,so they underwent laparoscop adrenalectomy too. The symptoms of primary aldosteronism were ameliorated to various extents in 57 cases after treatment. Histopathological examination confirmed adrenal adenoma in 19 patients.adrenal micro-adenoma in 21 patients and adrenal nodular hyperplasia in 17 patients. Conclusions: Primary aldosteronism was diagnosised by adrenal imaging examination and the measurement of the hormone levels of peripheral and adrenal venous sampling. Laparoscopic adrenalectomy is the preferred surgical approach for adrenal adenoma,and the measurement of hormone levels of peripheral and adrenal venous sampling was the key of early diagnosis, early treatment and prevention of disease progression.%目的:探讨原发性醛固酮增多症的诊断及治疗.方法:回顾性分析63例原发性醛固酮增多症患者的临床资料.结果:63例均有不同程度高血压,低钾者58例,通过测定外周血及肾上腺静脉血的激素水平,19例为原发性醛固酮增多症腺瘤型,14例为肾上腺增生.19例腺瘤型直接行腹腔镜肾上腺切除术,增生及其余行外周血及肾

  11. Progress in aldosterone-induced myocardial fibrosis and mechanism underlying its signal transduction%醛固酮致心肌纤维化及其信号转导机制研究进展

    Institute of Scientific and Technical Information of China (English)

    谢永进

    2011-01-01

    心肌纤维化(myocardial fibrosis,MF)是高血压、心肌梗死、心力衰竭等多种心脏疾病终末阶段的共同病理改变,肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosterone system,RAAS)是MF发生发展的重要神经内分泌机制.醛固酮(aldosterone,ALD)导致MF信号转导的分子机制近年来取得了一些进展,信号网络相当复杂,有待进一步明确和深入研究.

  12. Evaluation of intravenous saline load test in diagnosis of primary aldosteronism%静脉盐水负荷试验在原发性醛固酮增多症诊断中的价值

    Institute of Scientific and Technical Information of China (English)

    薛声能; 雷娟; 唐菊英; 张少玲

    2012-01-01

    Objective To investigate the value of intravenous (i. v. ) saline load test in the diagnosis of primary aldosteronism. Methods From year 2006 to 2010, 47 patients clinically diagnosed with primary aldosteronism were performed i. v. saline load test, plasma and urinary aldosterone, and serum potassium were examined at the same time. 30 patients with essential hypertension were served as controls. Results Compared with the control group, patients with primary aldosteronism had higher plasma and urinary aldosterone. lower serum potassium. The inhibition ratio (13. 3 + 5. 6) % and the proportion of patients restrained (4. 3% ) after i. v. saline load test in primary aldosteronism group were lower than those in control group [ (78. 0?2.5)% and (93.3%), respectively]. The sensitivity and specificity of i. v. saline load test for primary aldosteronism were 95.7% (45/47) and 93. 3% (28/30). Conclusions The i. v. saline load test is a safe and reliable confirmatory test for the diagnosis of primary aldosteronism with a high sensitivity and specificity.%目的 探讨静脉盐水负荷试验在原发性醛固酮增多症诊断中的应用价值.方法 选择2006-2010年临床诊断为原发性醛固酮增多症的患者47例,行静脉盐水负荷试验并同时检测其血、尿醛固酮及血钾等生化指标.以30例原发性高血压患者作为对照组.结果 与对照组比较,原发性醛固酮增多症患者静脉盐水负荷试验前、后血醛固酮水平、24h尿醛固酮排量显著升高,血钾水平明显下降;原发性醛固酮增多症患者血醛固酮的抑制率[(13.3±5.6)%]和受抑制患者的比例(4.3%)明显低于对照组[分别为(78.0±12.5)%和(93.3%)],该试验对原发性醛固酮增多症诊断的敏感性和特异性分别为95.7%(45/47)和93.3%(28/30).结论 静脉盐水负荷试验是一项安全可靠的原发性醛固酮增多症确诊方法,其敏感性和特异性均较高.

  13. 盐水负荷试验对原发性醛固酮增多症的诊断价值%Diagnostic Value of Saline Load Test in Patients With Primary Aldosteronism

    Institute of Scientific and Technical Information of China (English)

    王立雪; 母义明; 巴建明; 窦京涛; 吕朝晖; 王先令; 杜锦; 杨国庆; 陆菊明

    2016-01-01

    目的:评价盐水负荷试验对于原发性醛固酮增多症(PHA)的诊断价值。方法:回顾性分析1994-06至2012-05我院72例PHA患者(PHA组)和44例排除PHA的原发性高血压(EH)患者(EH组)的临床资料。并应用受试者工作曲线(ROC曲线)对盐水负荷试验前后血浆醛固酮水平及试验后血浆醛固酮/肾素活性比值进行评价,分析其诊断效能,得出最佳诊断切点。结果:试验后血浆醛固酮水平ROC曲线下面积为0.759,敏感性为74.6%,特异性为63.6%。试验后血浆醛固酮/肾素活性比值ROC曲线下面积为0.899,敏感性为83.6%,特异性为88.6%,最佳诊断切点为111[ng/dl:ng/(ml·h)]。结论:盐水负荷试验后血浆醛固酮水平及血浆醛固酮/肾素活性比值,对于PHA均有诊断价值,试验后血浆醛固酮/肾素活性比值诊断效能更高。%Objective: To evaluate the diagnostic value of saline infusion test (SIT) in patients with primary aldosteronism (PHA). Methods: A total of 116 patients with PHA or essential hypertension (EH) treated in our hospital from 1994-06 to 2013-05 were retrospectively studied. The patients were divided into 2 groups: PHA group,n=72 and EH group, the patients with excluded PHA,n=44. post-SIT plasma levels of aldosterone and post-SIT ratio of aldosterone/renin activity were evaluated by ROC curve in order to analyze the diagnostic capability and the best diagnostic cut-off point. Results: The area under curve (AUC) by ROC for post-SIT aldosterone level was 0.759, the sensitivity and speciifcity were 74.6% and 63.6% respectively; AUC for post-SIT ratio of aldosterone/renin activity was 0.899, the sensitivity and speciifcity were 83.6% and 88.6% with the best diagnostic cut-off point at 111 [ng/dl:ng/(ml•h)]. Conclusion: Post-SIT plasma level of aldosterone and post-SIT ratio of aldosterone/renin activity had the diagnostic value of PHA; post-SIT ratio of aldosterone/renin activity

  14. Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists

    Science.gov (United States)

    2016-08-01

    Center for Substance Abuse Research Lewis Katz School of Medicine at Temple University 3500 N, Broad Street Philadelphia, PA 19140 AND ADDRESS(ES) 8...processes), affect the ability of opioid drugs to counteract pain. We predicted that one way of increasing the effectiveness of the pain-relieving... drugs would be to eliminate or reduce the activity of the chemokines by administering chemokine receptor antagonists (CRAs). The blockade of one or

  15. Potent and orally efficacious benzothiazole amides as TRPV1 antagonists.

    Science.gov (United States)

    Besidski, Yevgeni; Brown, William; Bylund, Johan; Dabrowski, Michael; Dautrey, Sophie; Harter, Magali; Horoszok, Lucy; Hu, Yin; Johnson, Dean; Johnstone, Shawn; Jones, Paul; Leclerc, Sandrine; Kolmodin, Karin; Kers, Inger; Labarre, Maryse; Labrecque, Denis; Laird, Jennifer; Lundström, Therese; Martino, John; Maudet, Mickaël; Munro, Alexander; Nylöf, Martin; Penwell, Andrea; Rotticci, Didier; Slaitas, Andis; Sundgren-Andersson, Anna; Svensson, Mats; Terp, Gitte; Villanueva, Huascar; Walpole, Christopher; Zemribo, Ronald; Griffin, Andrew M

    2012-10-01

    Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.

  16. Epiminocyclohepta[b]indole analogs as 5-HT6 antagonists

    DEFF Research Database (Denmark)

    Henderson, Alan J; Guzzo, Peter R; Ghosh, Animesh;

    2012-01-01

    A new series of epiminocyclohepta[b]indoles with potent 5-HT(6) antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT(6) receptor occupancy studies. The compound was found...... to have excellent oral absorption, a highly favorable PK profile and demonstrated pharmacodynamic interaction with the 5-HT(6) receptor as shown by ex vivo autoradiography....

  17. Exploration of a new series of PAR1 antagonists.

    Science.gov (United States)

    Planty, Bruno; Pujol, Chantal; Lamothe, Marie; Maraval, Catherine; Horn, Clemens; Le Grand, Bruno; Perez, Michel

    2010-03-01

    Two series of new PAR1 antagonists have been identified. The first incorporates a cinnamoylpiperidine motif and the second a cinnamoylpyridine pattern. The synthesis, biological activity and structure-activity relationship of these compounds are presented. In each series, one analog showed potent in vivo antithrombotic activity in a rat AV shunt model, with up to 53% inhibition at 1.25mpk iv for compound 30.

  18. Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine

    OpenAIRE

    Funder JW

    2013-01-01

    John W FunderPrince Henry's Institute, Clayton, Victoria, AustraliaAbstract: Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor (MR) antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more MR-specific. From a marginal role as a potassium-sparing diuretic, spironolactone was shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure, as ...

  19. Approaches to the rational design of selective melanocortin receptor antagonists

    Science.gov (United States)

    Hruby, Victor J; Cai, Minying; Nyberg, Joel; Muthu, Dhanasekaran

    2015-01-01

    Introduction When establishing the physiological roles of specific receptors in normal and disease states, it is critical to have selective antagonist ligands for each receptor in a receptor system with several subtypes. The melanocortin receptors have five subtypes referred to as the melanocortin 1 receptor, melanocortin 2 receptor, melanocortin 3 receptor, melanocortin 4 receptor and melanocortin 5 receptor, and they are of critical importance for many aspects of human health and disease. Areas covered This article reviews the current efforts to design selective antagonistic ligands for the five human melanocortin receptors summarizing the currently published orthosteric and allosteric antagonists for each of these receptors. Expert opinion Though there has been progress, there are still few drugs available that address the many significant biological activities and diseases that are associated with these receptors, which is possibly due to the lack of receptor selectivity that these designed ligands are currently showing. The authors believe that further studies into the antagonists’ 3D conformational and topographical properties in addition to future mutagenesis studies will provide greater insight into these ligands which could play a role in the treatment of various diseases in the future. PMID:22646078

  20. Synergistic and antagonistic drug combinations depend on network topology.

    Science.gov (United States)

    Yin, Ning; Ma, Wenzhe; Pei, Jianfeng; Ouyang, Qi; Tang, Chao; Lai, Luhua

    2014-01-01

    Drug combinations may exhibit synergistic or antagonistic effects. Rational design of synergistic drug combinations remains a challenge despite active experimental and computational efforts. Because drugs manifest their action via their targets, the effects of drug combinations should depend on the interaction of their targets in a network manner. We therefore modeled the effects of drug combinations along with their targets interacting in a network, trying to elucidate the relationships between the network topology involving drug targets and drug combination effects. We used three-node enzymatic networks with various topologies and parameters to study two-drug combinations. These networks can be simplifications of more complex networks involving drug targets, or closely connected target networks themselves. We found that the effects of most of the combinations were not sensitive to parameter variation, indicating that drug combinational effects largely depend on network topology. We then identified and analyzed consistent synergistic or antagonistic drug combination motifs. Synergistic motifs encompass a diverse range of patterns, including both serial and parallel combinations, while antagonistic combinations are relatively less common and homogenous, mostly composed of a positive feedback loop and a downstream link. Overall our study indicated that designing novel synergistic drug combinations based on network topology could be promising, and the motifs we identified could be a useful catalog for rational drug combination design in enzymatic systems.

  1. Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.

    Directory of Open Access Journals (Sweden)

    Sachiko Yamada

    Full Text Available Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7 in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1, a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.

  2. IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

    Science.gov (United States)

    Shekhar, Tanmay M.; Miles, Mark A.; Gupte, Ankita; Taylor, Scott; Tascone, Brianna; Walkley, Carl R.; Hawkins, Christine J.

    2016-01-01

    Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors. PMID:27129149

  3. Histamine H1 antagonists and clinical characteristics of febrile seizures

    Directory of Open Access Journals (Sweden)

    Zolaly MA

    2012-03-01

    Full Text Available Mohammed A ZolalyDepartment of Pediatrics, College of Medicine, Taibah University, Al-Madinah Al-Munawarah, Kingdom of Saudi ArabiaBackground: The purpose of this study was to determine whether seizure susceptibility due to antihistamines is provoked in patients with febrile seizures.Methods: The current descriptive study was carried out from April 2009 to February 2011 in 250 infants and children who visited the Madinah Maternity and Children's Hospital as a result of febrile convulsions. They were divided into two groups according to administration of antihistamines at the onset of fever.Results: Detailed clinical manifestations were compared between patients with and without administration of antihistamines. The time from fever detection to seizure onset was significantly shorter in the antihistamine group than that in the nonantihistamine group, and the duration of seizures was significantly longer in the antihistamine group than in the nonantihistamine group. No significant difference was found in time from fever detection to seizure onset or seizure duration between patients who received a first-generation antihistamine and those who received a second-generation antihistamine.Conclusion: Due to their central nervous system effects, H1 antagonists should not be administered to patients with febrile seizures and epilepsy. Caution should be exercised regarding the use of histamine H1 antagonists in young infants, because these drugs could potentially disturb the anticonvulsive central histaminergic system.Keywords: antihistamine, nonantihistamine, histamine H1 antagonist, febrile seizures

  4. Receptor discrimination and control of agonist-antagonist binding.

    Science.gov (United States)

    Tallarida, R J

    1995-08-01

    The law of mass action is the common model for the interaction of agonist and antagonist compounds with cellular receptors. Parameters of the interaction, obtained from functional and radioligand-binding studies, allow discrimination and subtyping of receptors and aid in understanding specific mechanisms. This article reviews the theory and associated mathematical models and graphical transformations of data that underlie the determination of receptor parameters. The main theory assumes that agonist and antagonist compounds bind to cells that have a fixed number of receptors and provides the framework for obtaining drug-receptor parameters from data and their graphical transformations. Conditions that produce a change in receptor number, a newer concept in pharmacology, can have an important effect on the parameter values derived in the usual way. This review concludes with a discussion of the quantitative study of receptor-mediated feedback control of endogenous ligands, a very new topic with potentially important implications for understanding antagonist effectiveness, loss of control, and chaos in regulated mass action binding.

  5. μ Opioid receptor: novel antagonists and structural modeling

    Science.gov (United States)

    Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

    2016-02-01

    The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.

  6. Newer calcium channel antagonists and the treatment of hypertension.

    Science.gov (United States)

    Cummins, D F

    1999-07-01

    Calcium channel antagonists have become popular medications for the management of hypertension. These agents belong to the diphenylalkylamine, benzothiazepine, dihydropyridine, or tetralol chemical classes. Although the medications share a common pharmacological mechanism in reducing peripheral vascular resistance, clinical differences between the sub-classes can be linked to structural profiles. This heterogeneity is manifested by differences in vascular selectivity, effects on cardiac conduction and adverse events. The lack of differentiation between calcium channel antagonists in clinical trials has contributed to uncertainty associated with their impact on morbidity and mortality. Data from more recent studies in specific patient populations underscores the importance of investigating these antihypertensives as individual agents. A proposed therapeutic classification system suggests that newer agents should share the slow onset and long-acting antihypertensive effect of amlodipine. Additionally, a favourable trough-to-peak ratio has been recommended as an objective measurement of efficacy. The newer drugs, barnidipine and lacidipine, have a therapeutic profile similar to amlodipine, but trough-to-peak ratios are not substantially greater than the recommended minimum of 0.50. Aranidipine, cilnidipine and efonidipine have unique pharmacological properties that distinguish them from traditional dihydropyridines. Although clinical significance is unconfirmed, these newer options may be beneficial for patients with co-morbid conditions that preclude use of older antagonists.

  7. High risk of adrenal toxicity of N1-desoxy quinoxaline 1,4-dioxide derivatives and the protection of oligomeric proanthocyanidins (OPC) in the inhibition of the expression of aldosterone synthetase in H295R cells.

    Science.gov (United States)

    Wang, Xu; Yang, Chunhui; Ihsan, Awais; Luo, Xun; Guo, Pu; Cheng, Guyue; Dai, Menghong; Chen, Dongmei; Liu, Zhenli; Yuan, Zonghui

    2016-02-01

    Quinoxaline 1,4-dioxide derivatives (QdNOs) with a wide range of biological activities are used in animal husbandry worldwide. It was found that QdNOs significantly inhibited the gene expression of CYP11B1 and CYP11B2, the key aldosterone synthases, and thus reduced aldosterone levels. However, whether the metabolites of QdNOs have potential adrenal toxicity and the role of oxidative stress in the adrenal toxicity of QdNOs remains unclear. The relatively new QdNOs, cyadox (CYA), mequindox (MEQ), quinocetone (QCT) and their metabolites, were selected for elucidation of their toxic mechanisms in H295R cells. Interestingly, the results showed that the main toxic metabolites of QCT, MEQ, and CYA were their N1-desoxy metabolites, which were more harmful than other metabolites and evoked dose and time-dependent cell damage on adrenal cells and inhibited aldosterone production. Gene and protein expression of CYP11B1 and CYP11B2 and mRNA expression of transcription factors, such as NURR1, NGFIB, CREB, SF-1, and ATF-1, were down regulated by N1-desoxy QdNOs. The natural inhibitors of oxidant stress, oligomeric proanthocyanidins (OPC), could upregulate the expression of diverse transcription factors, including CYP11B1 and CYP11B2, and elevated aldosterone levels to reduce adrenal toxicity. This study demonstrated for the first time that N1-desoxy QdNOs have the potential to be the major toxic metabolites in adrenal toxicity, which may shed new light on the adrenal toxicity of these fascinating compounds and help to provide a basic foundation for the formulation of safety controls for animal products and the design of new QdNOs with less harmful effects.

  8. Aldosterone and thyroid hormone modulation of alpha 1-, beta 1-mRNA, and Na,K-pump sites in rabbit distal colon epithelium. Evidence for a novel mechanism of escape from the effect of hyperaldosteronemia.

    Science.gov (United States)

    Wiener, H; Nielsen, J M; Klaerke, D A; Jørgensen, P L

    1993-05-01

    Aldosterone and thyroid hormone regulation of Na,K-pump biosynthesis has been examined in the distal colon epithelium of rabbits. Qualitative analysis of alpha-subunit isoform distribution (alpha 1, alpha 2, alpha 3) detected only the alpha 1-mRNA in the distal colon epithelium and outer renal medulla, while all three isoforms were observed in rabbit brain. A low-sodium diet led to a rise in serum aldosterone from 0.6 nM to 1.4-1.9 nM and an increase of alpha 1-mRNA to 162%, beta 1-mRNA to 120%, and the number of Na,K-pump units as determined by specific [3H]-ouabain binding to 182% of control by the second day of the diet. While aldosterone levels remained elevated, a spontaneous decrease in serum levels of T3 and T4 to 50-60% of control from the third day of the diet was followed by downregulation of beta 1-mRNA to 55-67%, alpha 1-mRNA to 63-105%, and of [3H]-ouabain binding to 103% of control, suggesting that a reduced rate of synthesis of the beta 1-subunit is rate limiting for Na,K-pump biosynthesis. Substitution with T3 (10 micrograms/kg) at the seventh day with transient restoration of serum T3 to control levels, led to rapid accumulation of beta 1-mRNA to 152%, of alpha 1-mRNA to 135%, and of the number of Na,K-pump units to 153% of control. This is consistent with thyroid hormone having a permissive role for the aldosterone stimulation of Na,K-pump biosynthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

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

    Science.gov (United States)

    Borghi, Claudio; Rossi, Francesco

    2015-12-01

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

  10. Aliskiren suppresses the renin–angiotensin–aldosterone system and reduces blood pressure and albuminuria in elderly chronic kidney disease patients with hypertension

    Directory of Open Access Journals (Sweden)

    Morishita Y

    2012-09-01

    Full Text Available Yoshiyuki Morishita,1 Toshihiro Yasui,2 Akihiko Numata,1 Akira Onishi,1 Kenichi Ishibashi,3 Eiji Kusano11Department of Internal Medicine, Jichi Medical University, Shimotsuke, Japan; 2National Health Insurance Yukawa Clinic, Niimi, Japan; 3Department of Medical Physiology, Meiji Pharmaceutical University, Tokyo, JapanBackground: We investigated the effects of aliskiren in terms of its inhibition of the renin–angiotensin–aldosterone system (RAAS as well as that on blood pressure (BP, and renal and cardiac protection in elderly chronic kidney disease (CKD patients with hypertension.Methods: Nineteen elderly CKD patients (nine males, ten females, aged 74.6 ± 5.8 years were assigned to receive 150 mg/day of aliskiren added to existing antihypertensives for 6 months. Changes in plasma renin activity (PRA, angiotensin I (Ang I, angiotensin II (Ang II, aldosterone (Ald, BP, estimated glomerular filtration rate (eGFR, urine albumin/creatinine ratio (UACR, left ventricular ejection fraction (LVEF, interventricular septum thickness (IVST, left ventricular posterior wall thickness (LVPWT, and plasma brain natriuretic peptide (BNP levels were evaluated.Results: Aliskiren suppressed the RAAS as follows: PRA 1.3 ± 1.0 to 0.3 ± 0.3 ng/mL/hour, P < 0.05; Ang I 59.5 ± 32.1 to 26.0 ± 17.3 pg/mL, P < 0.05; Ang II 58.4 ± 62.1 to 14.3 ± 9.0 pg/mL, P < 0.05; and Ald 86.1 ± 38.3 to 80.1 ± 52.6 pg/mL, not significant (NS. Aliskiren reduced BP (153.6/77.2 ± 14.9/10.4 to 130.9/72.2 ± 15.6/9.9 mmHg, P < 0.05. It also reduced UACR (747.1 ± 1121.4 to 409.6 ± 636.8 mg/g, P < 0.05, whereas it did not change eGFR (52.1 ± 29.2 to 51.2 ± 29.3 mL/min/1.73 m2, NS, LVEF (66.8 ± 7.9 to 66.5% ± 6.8%, NS, IVST (10.1 ± 1.8 to 9.9 ± 1.8 mm, NS, LVPWT (10.0 ± 1.6 mm to 10.0 ± 1.4 mm, NS, or BNP (48.2 ± 46.0 to 54.9 ± 41.1 pg/mL, NS.Conclusion: Aliskiren was effective for BP control and reduced UACR while maintaining eGFR and heart function in elderly CKD

  11. Kappa opioid receptor antagonist and N-methyl-D- aspartate receptor antagonist affect dynorphin- induced spinal cord electrophysiologic impairment

    Institute of Scientific and Technical Information of China (English)

    Yu Chen; Liangbi Xiang; Jun Liu; Dapeng Zhou; Hailong Yu; Qi Wang; Wenfeng Han; Weijian Ren

    2012-01-01

    The latencies of motor- and somatosensory-evoked potentials were prolonged to different degrees, and wave amplitude was obviously decreased, after injection of dynorphin into the rat subarachnoid cavity.The wave amplitude and latencies of motor- and somatosensory-evoked potentials were significantly recovered at 7 and 14 days after combined injection of dynorphin and either the kappa opioid receptor antagonist nor-binaltorphimine or the N-methyl-D-aspartate receptor antagonist MK-801.The wave amplitude and latency were similar in rats after combined injection of dynorphin and nor-binaltorphimine or MK-801.These results suggest that intrathecal injection of dynorphin causes damage to spinal cord function.Prevention of N-methyl-D-aspartate receptor or kappa receptor activation lessened the injury to spinal cord function induced by dynorphin.

  12. Aldosterone synthase C-344T, angiotensin II type 1 receptor A1166C and 11- hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha, India

    Indian Academy of Sciences (India)

    Manisha Patnaik; Pallabi Pati; Surendra N. Swain; Manoj K. Mohapatra; Bhagirathi Dwibedi; Shantanu K. Kar; Manoranjan Ranjit

    2014-12-01

    Essential hypertension which accounts 90–95% of the total hypertension cases is affected by both genetic and environmental factors. This study was undertaken to investigate the association of aldosterone synthase C-344T, angiotensin II type I receptor A1166C and 11- hydroxysteroid dehydrogenase type 2 G534A polymorphisms with essential hypertension in the population of Odisha, India. A total of 246 hypertensive subjects (males, 159; females, 87) and 274 normal healthy individuals (males, 158; females, 116) were enrolled in this study based on the inclusion and exclusion criteria. Analysis of genetic and biochemical data revealed that in this population the CT and TT genotypes of aldosterone synthase C-344T polymorphism, frequency of alcohol consumption and aldosterone levels were significantly high among the total as well as male hypertensives, while the AC and CC genotypes of angiotensin II type I receptor A1166C polymorphism were significantly high among the total as well as female hypertensives. High density lipoprotein levels were higher in male hypertensives.

  13. Aldosterone synthase C-344T, angiotensin II type 1 receptor A1166C and 11- hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha, India

    Indian Academy of Sciences (India)

    Manisha Patnaik; Pallabi Pati; Surendra N. Swain; Manoj K. Mohapatra; Bhagirathi Dwibedi; Shantanu K. Kar; Manoranjan Ranjit

    2015-06-01

    Essential hypertension which accounts 90–95% of the total hypertension cases is affected by both genetic and environmental factors. This study was undertaken to investigate the association of aldosterone synthase C-344T, angiotensin II type I receptor A1166C and 11- hydroxysteroid dehydrogenase type 2 G534A polymorphisms with essential hypertension in the population of Odisha, India. A total of 246 hypertensive subjects (males, 159; females, 87) and 274 normal healthy individuals (males, 158; females, 116) were enrolled in this study based on the inclusion and exclusion criteria. Analysis of genetic and biochemical data revealed that in this population the CT and TT genotypes of aldosterone synthase C-344T polymorphism, frequency of alcohol consumption and aldosterone levels were significantly high among the total as well as male hypertensives, while the AC and CC genotypes of angiotensin II type I receptor A1166C polymorphism were significantly high among the total as well as female hypertensives. High density lipoprotein levels were higher in male hypertensives.

  14. Clinical observation and analysis of aldosterone escape in patients with non-diabetic nephropathy by RASI-therapy%非糖尿病慢性肾病患者RASI治疗后醛固酮逃逸现象

    Institute of Scientific and Technical Information of China (English)

    杨庆春; 罗慧洁; 柏琳; 施海涛; 张志任

    2016-01-01

    Objective To investigate the incidence and influencing factors of aldosterone escape in patients with non-diabetic nephropathy by RASI-therapy. Methods A total of 104 patients with non-diabetic nephropathy were treated with ARB or combination therapy of ACEI and ARB in a mean follow-up period of 12 months. Aldosterone escape was determined according to the change of plasma aldosterone concentration before and after treatment during 6-month and 12-month ACEI/ARB treatment, while the influencing factors of aldosterone escape in patients with non-diabetic nephropathy was also analyzed after therapy with RASI . Results In 12 months, the incidence of aldosterone escape was significantly higher than that in 6 months (26.92% vs. 14.42%, P = 0.007). After 12-month treatment, the difference was statistically significant in incidence of aldosterone escape among different stages of CKD (P = 0.027). Compared with 6-month incidence of aldosterone escape in the losartan group, 12-month incidence increased evidently (P = 0.020). The Ald level was positively correlated with urinary protein excretion and the Scr level (r = 0.431, P = 0.003 and r = 0.336, P = 0.009, respectively), and negetively correlated with levels of the eGFR (r = -0.275, P = 0.006). Univariate Logistic regression demonstrated that risk factors of aldosterone escape included pre-treatment values of the urinary protein excretion (OR = 3.671, P = 0.028) and the eGFR (OR = 0.972, P = 0.019). Multivariate Logistic model revealed pre-treatment values of the eGFR was positively associated with aldosterone escape (OR = 0.970, P = 0.012). Conclusion The incidence of the aldosterone escape increases along with the time of treatment. Renal function has correlated with aldosterone escape and pre-treatment value of the eGFR is an independent risk factor of aldosterone escape.%目的:研究非糖尿病慢性肾病(CKD)患者醛固酮(Ald)逃逸的发生率及影响因素分析。方