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https://www.readbyqxmd.com/read/28814143/ly3045697-results-from-two-randomized-clinical-trials-of-a-novel-inhibitor-of-aldosterone-synthase
#1
Joanne Sloan-Lancaster, Eyas Raddad, Amy Flynt, Yan Jin, James Voelker, Jeffrey W Miller
INTRODUCTION: LY3045697 is a potent and selective aldosterone synthase (CYP11B2) inhibitor that was developed as a safer alternative to mineralocorticoid receptor antagonists. Effects of LY3045697 on aldosterone and cortisol synthesis, as well as potassium ion homeostasis, were evaluated in two clinical studies in healthy subjects. MATERIALS AND METHODS: Two incomplete, placebo-controlled crossover-design clinical studies examined safety, pharmacodynamics, and pharmacokinetics under single and repeated dose conditions in healthy subjects...
July 2017: Journal of the Renin-angiotensin-aldosterone System: JRAAS
https://www.readbyqxmd.com/read/28808323/stress-hormone-rapidly-tunes-synaptic-nmda-receptor-through-membrane-dynamics-and-mineralocorticoid-signalling
#2
Lenka Mikasova, Hui Xiong, Amber Kerkhofs, Delphine Bouchet, Harm J Krugers, Laurent Groc
Stress hormones, such as corticosteroids, modulate the transmission of hippocampal glutamatergic synapses and NMDA receptor (NMDAR)-dependent synaptic plasticity, favouring salient behavioural responses to the environment. The corticosterone-induced synaptic adaptations partly rely on changes in NMDAR signalling, although the cellular pathway underlying this effect remains elusive. Here, we demonstrate, using single molecule imaging and electrophysiological approaches in hippocampal neurons, that corticosterone specifically controls GluN2B-NMDAR surface dynamics and synaptic content through mineralocorticoid signalling...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28801620/a-novel-aldosterone-antagonist-limits-renal-injury-in-5-6-nephrectomy
#3
Clarice K Fujihara, M C Kowala, M D Breyer, Claudia R Sena, Mariliza V Rodrigues, Simone C A Arias, Camilla Fanelli, Denise M Malheiros, P K Jadhav, Chahrzad Montrose-Rafizadeh, Jose E Krieger, Roberto Zatz
Aldosterone antagonists slow the progression of chronic kidney disease (CKD), but their use is limited by hyperkalemia, especially when associated with RAS inhibitors. We examined the renoprotective effects of Ly, a novel non-steroidal mineralocorticoid receptor (MR) blocker, through two experimental protocols: In Protocol 1, male Munich-Wistar rats underwent 5/6 renal ablation (Nx), being divided into: Nx+V, receiving vehicle, Nx+Eple, given eplerenone, 150 mg/kg/day, and Nx+Ly, given Ly, 20 mg/kg/day...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28798899/diagnosed-a-patient-with-central-serous-chorioretinopathy-now-what-management-of-central-serous-chorioretinopathy
#4
Brian E Goldhagen, Raquel Goldhardt
PURPOSE OF REVIEW WHAT IS THE GOAL OF YOUR PAPER? WHAT QUESTIONS DID YOU SEEK TO ANSWER?: The goal of this paper is to provide a comprehensive review of the management options for central serous chorioretinopathy (CSCR). RECENT FINDINGS SUMMARIZE THE LATEST RESEARCH ON YOUR TOPIC: The majority of cases of acute CSCR may be managed with observation and cessation of corticosteroids, if possible, as well as life-style modifications including stress reduction and control of hypertension...
June 2017: Current Ophthalmology Reports
https://www.readbyqxmd.com/read/28797603/chronic-traumatic-stress-impairs-memory-in-mice-potential-roles-of-acetylcholine-neuroinflammation-and-corticotropin-releasing-factor-expression-in-the-hippocampus
#5
Ami Bhakta, Kartheek Gavini, Euitaek Yang, Lani Lyman-Henley, Kodeeswaran Parameshwaran
Chronic stress in humans can result in multiple adverse psychiatric and neurobiological outcomes, including memory deficits. These adverse outcomes can be more severe if each episode of stress is very traumatic. When compared to acute or short term stress relatively little is known about the effects of chronic traumatic stress on memory and molecular changes in hippocampus, a brain area involved in memory processing. Here we studied the effects of chronic traumatic stress in mice by exposing them to adult Long Evan rats for 28 consecutive days and subsequently analyzing behavioral outcomes and the changes in the hippocampus...
August 8, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28797006/amiloride-is-effective-in-the-management-of-abiraterone-induced-mineralocorticoid-excess-syndrome-without-interfering-with-its-antineoplastic-activity
#6
Francesca Bedussi, Diego Galli, Martina Fragni, Francesca Valcamonico, Elisa Rossini, Alberto Dalla Volta, Sara Vezzoli, Elisa Roca, Vittorio Ferrari, Barbara Lazzari, Maurizio Memo, Sandra Sigala, Alfredo Berruti
BACKGROUND: The administration of abiraterone acetate (abiraterone) leads to an adrenocorticotropic hormone (ACTH)-driven increase in mineralocorticoid hormones, requiring glucocorticoid supplementation that may stimulate the growth of prostate cancer (PCa). Amiloride is a drug that selectively reduces the aldosterone-sensitive Na+/K+ exchange and could be effective in the management of mineralocorticoid excess syndrome (MCES). METHODS: The efficacy of amiloride + hydrochlorothiazide (HCT) in the clinical management of abiraterone-induced MCES was assessed in 5 consecutive patients with castration-resistant PCa (CRPC)...
August 11, 2017: Pharmacology
https://www.readbyqxmd.com/read/28794569/cortisol-homeostasis-in-the-epidermis-is-influenced-by-topical-corticosteroids-in-patients-with-atopic-dermatitis
#7
Mototsugu Fukaya
BACKGROUND: The skin produces cortisol by itself and regulates its own proliferation and differentiation. There is a possibility that topical corticosteroids (TCSs) influence the cortisol homeostasis in the skin. AIMS AND OBJECTIVES: The author described the density and distribution of cortisol and its parties in the epidermis after application of topical steroids immunohistologically. MATERIALS AND METHODS: The forearm skin was biopsied before and after 2 weeks' application of clobetasol propionate 0...
July 2017: Indian Journal of Dermatology
https://www.readbyqxmd.com/read/28791529/effects-of-raas-inhibitors-in-patients-with-kidney-disease
#8
REVIEW
Fan Zhang, Hong Liu, Di Liu, Yexin Liu, Huiqiong Li, Xia Tan, Fuyou Liu, Youming Peng, Hongqing Zhang
Proteinuria and decline of renal function are associated with progression of kidney disease. The Renin Angiotensin Aldosterone System (RAAS) plays an important role in blood pressure regulation, fluid volume, and sodium balance. Overactivity of RAAS contributes to the pathogenesis of a variety of clinical conditions including progress of chronic kidney disease (CKD). This review summarizes the use of RAAS inhibitors as dual therapy or monotherapy in different stages of kidney disease. Experimental and clinical studies have demonstrated RAAS inhibitors prevent proteinuria, kidney fibrosis and slow decline of renal function and thus play a protective role in both early and end stages of kidney disease...
August 8, 2017: Current Hypertension Reports
https://www.readbyqxmd.com/read/28780577/drug-treatment-effects-on-outcomes-in-heart-failure-with-preserved-ejection-fraction-a-systematic-review-and-meta-analysis
#9
Sean Lee Zheng, Fiona T Chan, Adam A Nabeebaccus, Ajay M Shah, Theresa McDonagh, Darlington O Okonko, Salma Ayis
BACKGROUND: Clinical drug trials in patients with heart failure and preserved ejection fraction have failed to demonstrate improvements in mortality. METHODS: We systematically searched Medline, Embase and the Cochrane Central Register of Controlled Trials for randomised controlled trials (RCT) assessing pharmacological treatments in patients with heart failure with left ventricular (LV) ejection fraction≥40% from January 1996 to May 2016. The primary efficacy outcome was all-cause mortality...
August 5, 2017: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/28777913/enhanced-stress-response-in-5-ht1ar-overexpressing-mice-altered-hpa-function-and-hippocampal-long-term-potentiation
#10
Fuencisla Pilar-Cuellar, Rebeca Vidal Casado, Alvaro Diaz, Emilio Garro-Martinez, Raquel Linge, Elena Castro, Robert Haberzettl, Heidrun Fink, Bettina Bert, Jan Brosda, Beatriz Romero, Benedicto Crespo Facorro, Angel Pazos
Postsynaptic 5-HT1A receptors (5-HT1AR) play an important role in anxiety and stress, although their contribution is still controversial. Previous studies report that mice overexpressing postsynaptic 5-HT1ARs show no changes in basal anxiety, though the influence of stress conditions has not been addressed yet. In this study, we used this animal model to evaluate the role of 5-HT1ARs in anxiety response after pre-exposition to an acute stressor. Under basal conditions, 5-HT1AR overexpressing animals presented high corticosterone levels and a lower mineralocorticoid/glucocorticoid receptor ratio...
August 4, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28771453/nonsteroidal-mineralocorticoid-antagonists-in-diabetic-kidney-disease
#11
Farheen K Dojki, George Bakris
PURPOSE OF REVIEW: Current data highlight the pathological aspects of excess aldosterone in promoting glomerular hypertrophy, glomerulosclerosis, and proteinuria in diabetic kidney disease (DKD). The role of nonsteroidal mineralocorticoid receptor antagonists (MRAs) in DKD is being evaluated in ongoing clinical trials. RECENT FINDINGS: Recent studies demonstrate beneficial effects of adding MRAs to the treatment regimen of patients with type 2 diabetes with nephropathy...
September 2017: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/28769873/targeting-obesity-and-diabetes-to-treat-heart-failure-with-preserved-ejection-fraction
#12
REVIEW
Raffaele Altara, Mauro Giordano, Einar S Nordén, Alessandro Cataliotti, Mazen Kurdi, Saeed N Bajestani, George W Booz
Heart failure with preserved ejection fraction (HFpEF) is a major unmet medical need that is characterized by the presence of multiple cardiovascular and non-cardiovascular comorbidities. Foremost among these comorbidities are obesity and diabetes, which are not only risk factors for the development of HFpEF, but worsen symptoms and outcome. Coronary microvascular inflammation with endothelial dysfunction is a common denominator among HFpEF, obesity, and diabetes that likely explains at least in part the etiology of HFpEF and its synergistic relationship with obesity and diabetes...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28759940/impact-of-aldosterone-synthase-inhibitor-fad286-on-steroid-hormone-profile-in-human-adrenocortical-cells
#13
Coy Brunssen, Anja Hofmann, Mirko Peitzsch, Annika Frenzel, Christian G Ziegler, Nicholas F Brown, Steven M Weldon, Graeme Eisenhofer, Holger S Willenberg, Stefan R Bornstein, Henning Morawietz
Inhibition of aldosterone synthase (CYP11B2) is an alternative treatment option to mineralocorticoid receptor antagonism to prevent harmful aldosterone effects. FAD286 is the best characterized aldosterone synthase inhibitor. However, to date, no study has used sensitive liquid chromatography-tandem mass spectrometry to characterize in detail the effect of FAD286 on the secreted steroid hormone profile of adrenocortical cells. Basal aldosterone production in NCI-H295R cells was detectable and 9-fold elevated after stimulation with angiotensin II...
July 31, 2017: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
https://www.readbyqxmd.com/read/28756533/long-term-spironolactone-treatment-reduces-coronary-trpc-expression-vasoconstriction-and-atherosclerosis-in-metabolic-syndrome-pigs
#14
Wennan Li, Xingjuan Chen, Ashley M Riley, S Christopher Hiett, Constance J Temm, Eleni Beli, Xin Long, Saikat Chakraborty, Mouhamad Alloosh, Fletcher A White, Maria B Grant, Michael Sturek, Alexander G Obukhov
Coronary transient receptor potential canonical (TRPC) channel expression is elevated in metabolic syndrome (MetS). However, differential contribution of TRPCs to coronary pathology in MetS is not fully elucidated. We investigated the roles of TRPC1 and TRPC6 isoforms in coronary arteries of MetS pigs and determined whether long-term treatment with a mineralocorticoid receptor inhibitor, spironolactone, attenuates coronary TRPC expression and associated dysfunctions. MetS coronary arteries exhibited significant atherosclerosis, endothelial dysfunction, and increased histamine-induced contractions...
September 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28750542/clinical-presentation-predictors-and-outcomes-among-mineralocorticoid-receptor-antagonist-mra-eligible-acute-heart-failure-patients-in-the-heart-function-assessment-registry-trial-in-saudi-arabia-hearts
#15
Mostafa Q AlShamiri, Khalid F AlHabib, Waleed AlHabeeb, Ismail R Raslan, Anhar Ullah, Abdelfatah A Elasfar, Fayez Alshaer, Hanan Albackr, Layth Mimish, Ali Almasood, Saleh AlGhamdi, Abdullah Ghabashi
Mineralocorticoid receptor antagonist (MRA) therapy is indicated after myocardial infarction in patients with acute heart failure (AHF) with an ejection fraction ≤40% and lacking contraindications. We analyzed clinical presentations, predictors, and outcomes of MRA-eligible patients within a prospective registry of patients with AHF from 18 hospitals in Saudi Arabia, from 2009 to 2010. For this subgroup, mortality rates were followed until 2013, and the clinical characteristics, management, predictors, and outcomes were compared between MRA-treated and non-MRA-treated patients...
January 1, 2017: Angiology
https://www.readbyqxmd.com/read/28746811/the-acute-effects-of-different-spironolactone-doses-on-cardiac-function-in-streptozotocin-induced-diabetic-rats
#16
Aleksandra Vranic, Stefan Simovic, Petar Ristic, Tamara R Nikolic, Isidora Stojic, Ivan M Srejovic, Vladimir I Zivkovic, Vladimir Jakovljevic, Dusan Djuric
Currently, cardiovascular diseases are leading cause of global mortality, while diabetes mellitus remains an important cause of cardiovascular morbidity. Findings suggest that obesity and diabetes mellitus are closely interconnected with high aldosterone levels, while mineralocorticoid receptors antagonist therapy has shown positive effects on cardiovascular complications associated with diabetes mellitus. A recent study showed that patients with diabetes mellitus treated with mineralocorticoid receptors antagonist have improved coronary microvascular function, leading to improved diastolic dysfunction...
July 26, 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28744670/rna-binding-protein-hur-enhances-mineralocorticoid-signaling-in-renal-kc3ac1-cells-under-hypotonicity
#17
Ingrid Lema, Larbi Amazit, Khadija Lamribet, Jérôme Fagart, Anne Blanchard, Marc Lombès, Nadia Cherradi, Say Viengchareun
Mineralocorticoid receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron. Herein, we decipher mechanisms by which hypotonicity increases MR expression in renal principal cells. We identify HuR (human antigen R), an mRNA-stabilizing protein, as an important posttranscriptional regulator of MR expression. Hypotonicity triggers a rapid and reversible nuclear export of HuR in renal KC3AC1 cells, as quantified by high-throughput microscopy. We also identify a key hairpin motif in the 3'-untranslated region of MR transcript, pivotal for the interaction with HuR and its stabilizing function...
July 25, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28734243/caveolin-1-related-autophagy-initiated-by-aldosterone-induced-oxidation-promotes-liver-sinusoidal-endothelial-cells-defenestration
#18
Xiaoying Luo, Dan Wang, Xuan Luo, Xintao Zhu, Guozhen Wang, Zuowei Ning, Yang Li, Xiaoxin Ma, Renqiang Yang, Siyi Jin, Yun Huang, Ying Meng, Xu Li
Aldosterone, with pro-oxidation and pro-autophagy capabilities, plays a key role in liver fibrosis. However, the mechanisms underlying aldosterone-promoted liver sinusoidal endothelial cells (LSECs) defenestration remain unknown. Caveolin 1 (Cav1) displays close links with autophagy and fenestration. Hence, we aim to investigate the role of Cav1-related autophagy in LSECs defenestration. We found the increase of aldosterone/MR (mineralocorticoid receptor) level, oxidation, autophagy, and defenestration in LSECs in the human fibrotic liver, BDL or hyperaldosteronism models; while antagonizing aldosterone or inhibiting autophagy relieved LSECs defenestration in BDL-induced fibrosis or hyperaldosteronism models...
July 13, 2017: Redox Biology
https://www.readbyqxmd.com/read/28733447/mineralocorticoid-receptor-antagonists-attenuate-exaggerated-exercise-pressor-reflex-responses-in-hypertensive-rats
#19
Ryan M Downey, Masaki Mizuno, Jere Holloway Mitchell, Wanpen Vongpatanasin, Scott A Smith
Exaggerated heart rate (HR) and blood pressure responses to exercise in hypertension are mediated, in part, by overactivity of the exercise pressor reflex (EPR). The mechanisms underlying this EPR dysfunction have not been fully elucidated. Previous studies have shown that stimulation of mineralocorticoid receptors (MR) with exogenous administration of aldosterone in normal, healthy rats reproduces the EPR overactivity characteristic of hypertensive animals. Conversely, the purpose of this study was to examine whether antagonizing MR with spironolactone (SPIR) or eplerenone (EPL) in decerebrated hypertensive rats ameliorates abnormal EPR function...
July 21, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28724838/csk-regulates-blood-pressure-by-controlling-the-synthetic-pathways-of-aldosterone
#20
Sung-Moon Kim, Ji-One Kang, Ji Eun Lim, Sue-Yun Hwang, Bermseok Oh
BACKGROUND: Blood pressure is regulated by a network of diverse physiological pathways. The C-terminal Src kinase (CSK) locus (15q24) is associated with blood pressure in various ethnic groups. It was recently reported thatCskinsufficiency increases blood pressure through Src. The mechanisms of hypertension inCsk(+/-)mice are examined further in this study.Methods and Results:To identify a causal component responsible for hypertension inCsk(+/-), the heart rate was measured by electrocardiogram and plasma volume by Evans blue dilution...
July 20, 2017: Circulation Journal: Official Journal of the Japanese Circulation Society
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