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https://www.readbyqxmd.com/read/27930384/the-endothelial-mineralocorticoid-receptor-mediator-of-the-switch-from-vascular-health-to-disease
#1
Ana P Davel, Imran J Anwar, Iris Z Jaffe
PURPOSE OF REVIEW: Endothelial dysfunction is an early feature of vascular disease induced by cardiovascular risk factors (CRFs). In growing populations with obesity, diabetes, hypertension, and heart failure, mineralocorticoid receptor antagonism improves endothelial function. This review summarizes recent advances in our understanding of the specific role of endothelial cell mineralocorticoid receptor in vascular function in health and disease. RECENT FINDINGS: Using transgenic mice with mineralocorticoid receptor expression specifically modulated in endothelial cells, recent studies support the emerging concept that while endothelial cell mineralocorticoid receptor may be protective in health, in the presence of CRFs, endothelial cell mineralocorticoid receptor activity contributes to endothelial dysfunction and progression of vascular disease...
December 7, 2016: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/27915044/a-novel-aldosterone-synthase-inhibitor-ameliorates-mortality-in-pressure-overload-mice-with-heart-failure
#2
Shinji Furuzono, Masaki Meguro, Satoru Miyauchi, Shinichi Inoue, Tsuyoshi Homma, Keisuke Yamada, Yoh-Ichi Tagawa, Futoshi Nara, Takahiro Nagayama
It has been elucidated that mineralocorticoid receptor antagonists reduce mortality in patients with congestive heart failure and post-acute myocardial infarction. A direct inhibition of aldosterone synthase (CYP11B2) is also expected to have therapeutic benefits equal in quality to mineralocorticoid receptor antagonists in terms of reducing mineralocorticoid receptor signaling. Therefore, we have screened our chemical libraries and identified a novel and potent aldosterone synthase inhibitor, 2,2,2-trifluoro-1-{4-[(4-fluorophenyl)amino]pyrimidin-5-y}-1-[1-(methylsulfonyl)piperidin-4-yl]ethanol (compound 1), by lead optimization...
November 30, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27912890/persistence-of-123-i-mibg-prognostic-capability-in-relation-to-medical-therapy-in-heart-failure-from-the-admire-hf-trial
#3
Ileana L Piña, Peter Carson, JoAnn Lindenfeld, W Tad Archambault, Arnold F Jacobson
(123)I-mIBG imaging has been evaluated to assess sympathetic function and prognosis in heart failure (HF). However, the effect of combined HF medical therapies on (123)I-mIBG uptake and its prognostic significance has not been previously examined. This analysis examined the relation between the intensity of guideline-directed HF medical therapy and global (123)I-mIBG cardiac uptake in the AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF) database. A second objective was to investigate whether this guideline-based therapy, measured by total medication doses, had the expected effect on outcome, that is, that patients with higher (123)I-mIBG cardiac uptake and more intensive medical therapy had the fewest outcome events...
October 31, 2016: American Journal of Cardiology
https://www.readbyqxmd.com/read/27905877/mineralocorticoid-receptor-antagonists-for-heart-failure-systematic-review-and-meta-analysis
#4
Nicolas M Berbenetz, Marko Mrkobrada
BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) have been associated with improved patient outcomes in patients with heart failure with reduced ejection fraction (HFrEF) but not preserved ejection fraction (HFpEF). We conducted a systematic review and meta-analysis of selective and nonselective MRAs in HFrEF and HFpEF. METHODS: We searched Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE. We included randomized controlled trials (RCT) of MRAs in adults with HFpEF or HFrEF if they reported data on major adverse cardiac events or drug safety...
December 1, 2016: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/27899856/effect-of-spironolactone-on-plasma-apelin-12-levels-in-patients-with-chronic-systolic-heart-failure
#5
Mustafa Topuz, Mehmet Cosgun, Oğuz Akkuş, Atilla Bulut, Omer Sen, Ayşe Nur Topuz, Murat Caylı
BACKGROUND: The aim of this study was to determine whether spironolactone therapy has an effect on serum apelin-12 levels in heart failure with reduced ejection fraction (HFrEF) patients. METHODS: Eighty outpatients previously diagnosed with HFrEF were enrolled in the current study. Included patients were taking only standard heart failure therapy (ST) (angiotensin converting enzyme or angiotensin receptor blocker, beta-blockers, loop diuretics and anticoagulant or antiagregan agents) without a mineralocorticoid receptor antagonists (MRA) because of its side effects, and were designated the non-MRA group; those patients taking 25 mg/daily spironolactone in addition to the ST were deemed the MRA group...
November 2016: Acta Cardiologica Sinica
https://www.readbyqxmd.com/read/27897427/structure-based-drug-design-of-mineralocorticoid-receptor-antagonists-to-explore-oxosteroid-receptor-selectivity
#6
Anneli Nordqvist, Gavin O'Mahony, Maria Fridén-Saxin, Marlene Fredenwall, Anders Hogner, Kenneth L Granberg, Anna Aagaard, Stefan Bäckström, Anders Gunnarsson, Tim Kaminski, Yafeng Xue, Anita Dellsén, Eva Hansson, Pia Hansson, Ida Ivarsson, Ulla Karlsson, Krister Bamberg, Majlis Hermansson, Jennie Georgsson, Bo Lindmark, Karl Edman
The mineralocorticoid receptor (MR) is a nuclear hormone receptor involved in regulation of body fluid and electrolyte homeostasis. In this study we explore selectivity triggers for a series of non-steroidal MR antagonists to improve selectivity over other members of the oxosteroid receptor family. A biaryl sulfonamide compound was identified in a high-throughput screening (HTS) campaign. The compound bound to MR with a pKi=6.6, but displayed poor selectivity over the glucocorticoid receptor (GR) and the progesterone receptor (PR)...
November 29, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27897263/principal-function-of-mineralocorticoid-signaling-suggested-by-constitutive-knockout-of-the-mineralocorticoid-receptor-in-medaka-fish
#7
Tatsuya Sakamoto, Madoka Yoshiki, Hideya Takahashi, Masayuki Yoshida, Yukiko Ogino, Toshitaka Ikeuchi, Tomoya Nakamachi, Norifumi Konno, Kouhei Matsuda, Hirotaka Sakamoto
As in osmoregulation, mineralocorticoid signaling is implicated in the control of brain-behavior actions. Nevertheless, the understanding of this role is limited, partly due to the mortality of mineralocorticoid receptor (MR)-knockout (KO) mice due to impaired Na(+) reabsorption. In teleost fish, a distinct mineralocorticoid system has only been identified recently. Here, we generated a constitutive MR-KO medaka as the first adult-viable MR-KO animal, since MR expression is modest in osmoregulatory organs but high in the brain of adult medaka as for most teleosts...
November 29, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27895136/recognition-and-management-of-resistant-hypertension
#8
REVIEW
Branko Braam, Sandra J Taler, Mahboob Rahman, Jennifer A Fillaus, Barbara A Greco, John P Forman, Efrain Reisin, Debbie L Cohen, Mohammad G Saklayen, S Susan Hedayati
Despite improvements in hypertension awareness and treatment, 30%-60% of hypertensive patients do not achieve BP targets and subsequently remain at risk for target organ damage. This therapeutic gap is particularly important to nephrologists, who frequently encounter treatment-resistant hypertension in patients with CKD. Data are limited on how best to treat patients with CKD and resistant hypertension, because patients with CKD have historically been excluded from hypertension treatment trials. First, we propose a consistent definition of resistant hypertension as BP levels confirmed by both in-office and out-of-office measurements that exceed appropriate targets while the patient is receiving treatment with at least three antihypertensive medications, including a diuretic, at dosages optimized to provide maximum benefit in the absence of intolerable side effects...
November 28, 2016: Clinical Journal of the American Society of Nephrology: CJASN
https://www.readbyqxmd.com/read/27893293/prevelence-of-primary-aldosteronism-in-an-urban-hypertensive-population
#9
Sandi-Jo Galati, Khadeen C Cheesman, Ryan Springer-Miller, Sarah M Hopkins, Lawrence Krakoff, Emilia Bagiella, Rachel A Zhuk, Tiffany K Ying, Chelsey Amer, Michael K Boyajian, W B Inabnet, Alice C Levine
OBJECTIVE: To determine the prevalence of primary aldosteronism (PA) in hypertensive patients presenting to the primary care clinic at The Mount Sinai Hospital, regardless of the degree of hypertension and to identify clinical criteria that should prompt screening for PA. METHODS: An aldosterone:renin ratio (ARR, cutoff ≥20, with plasma aldosterone concentration [PAC] ≥10 and suppressed renin) was used to prospectively screen 296 hypertensive patients (blood pressure [BP] ≥140/90) over the age of 18 from August 2012 through May 2013...
November 2016: Endocrine Practice
https://www.readbyqxmd.com/read/27892684/angiotensin-receptor-neprilysin-inhibitor-lcz696-pharmacology-pharmacokinetics-and-clinical-development
#10
Yue Hua, Ian Wang, Bin Liu, Darren J Kelly, Christopher Reid, Danny Liew, Yingchun Zhou, Bing H Wang
Heart failure still has a significant disease burden with poor outcomes worldwide despite advances in therapy. The standard therapies have been focused on blockade of renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid antagonists and the sympathetic nervous system with β-blockers. The natriuretic peptide system is a potential counter-regulatory system that promotes vasodilatation and natriuresis. Angiotensin receptor neprilysin inhibitors are a new class drug capable of blocking the renin-angiotensin-aldosterone system and enhancing the natriuretic peptide system to improve neurohormonal balance...
November 28, 2016: Future Cardiology
https://www.readbyqxmd.com/read/27889894/glucocorticoid-induced-leucine-zipper-in-central-nervous-system-health-and-disease
#11
REVIEW
Mythily Srinivasan, Debomoy K Lahiri
The central nervous system (CNS) is a large network of intercommunicating cells that function to maintain tissue health and homeostasis. Considerable evidence suggests that glucocorticoids exert both neuroprotective and neurodegenerative effects on the CNS. Glucocorticoids act by binding two related receptors in the cytoplasm, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The glucocorticoid receptor complex mediates cellular responses by transactivating target genes and by protein: protein interactions...
November 26, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27881672/mineralocorticoid-receptor-deficiency-in-macrophages-inhibits-atherosclerosis-by-affecting-foam-cell-formation-and-efferocytosis
#12
Zhu-Xia Shen, Xiao-Qing Chen, Xue-Nan Sun, Jian-Yong Sun, Wu-Chang Zhang, Xiao-Jun Zheng, Yu-Yao Zhang, Huan-Jing Shi, Jia-Wei Zhang, Chao Li, Jun Wang, Xu Liu, Sheng-Zhong Duan
Mineralocorticoid receptor (MR) has been considered as a potential target for treating atherosclerosis. However, the cellular and molecular mechanisms are not completely understood. We aim to explore the functions and mechanisms of macrophage MR in atherosclerosis. Atherosclerosis-susceptible LDLRKO chimeric mice with bone marrow cells from floxed control (FC) mice or from myeloid MR knockout (MRKO) mice were generated and fed with high cholesterol diet. Oil red O staining showed that MRKO decreased atherosclerotic lesion area in LDLRKO mice...
November 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27881412/renin-angiotensin-aldosterone-system-inhibitors-improve-membrane-stability-and-change-gene-expression-profiles-in-dystrophic-skeletal-muscles
#13
Jessica A Chadwick, Sayak Bhattacharya, Jeovanna Lowe, Noah Weisleder, Jill A Rafael-Fortney
Angiotensin-converting enzyme inhibitors and mineralocorticoid receptor (MR) antagonists are FDA approved drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) and are used to treat heart failure. Combined treatment with the angiotensin-converting enzyme inhibitor lisinopril and the non-specific MR antagonist spironolactone surprisingly improves skeletal muscle, in addition to heart function and pathology in a Duchenne muscular dystrophy mouse model. We recently demonstrated that MR is present in all limb and respiratory muscles and functions as a steroid hormone receptor in differentiated normal human skeletal muscle fibers...
November 23, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/27876790/stress-induces-a-shift-towards-striatum-dependent-stimulus-response-learning-via-the-mineralocorticoid-receptor
#14
Susanne Vogel, Floris Klumpers, Tobias Navarro Schröder, Krista T Oplaat, Harm J Krugers, Melly S Oitzl, Marian Joëls, Christian F Doeller, Guillén Fernández
Stress is assumed to cause a shift from flexible 'cognitive' memory to more rigid 'habit' memory. In the spatial memory domain, stress impairs place learning depending on the hippocampus whereas stimulus-response learning based on the striatum appears to be improved. While the neural basis of this shift is still unclear, previous evidence in rodents points towards cortisol interacting with the mineralocorticoid receptor (MR) to affect amygdala functioning. The amygdala is in turn assumed to orchestrate the stress-induced shift in memory processing...
November 23, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27872235/specific-aldosterone-synthase-inhibition-a-potential-improvement-over-mineralocorticoid-receptor-antagonism
#15
EDITORIAL
Markus P Schneider, Karl F Hilgers
No abstract text is available yet for this article.
November 21, 2016: Hypertension
https://www.readbyqxmd.com/read/27868385/impact-of-eplerenone-on-cardiovascular-outcomes-in-heart-failure-patients-with-hypokalaemia
#16
Patrick Rossignol, Nicolas Girerd, George Bakris, Orly Vardeny, Brian Claggett, John J V McMurray, Karl Swedberg, Henry Krum, Dirk J van Veldhuisen, Harry Shi, Sean Spanyers, John Vincent, Renaud Fay, Zohra Lamiral, Scott D Solomon, Faiez Zannad, Bertram Pitt
AIMS: Although hypokalaemia is common among patients with heart failure (HF), the prognostic significance of baseline hypokalaemia and hypokalaemia during follow-up in HF patients receiving a mineralocorticoid receptor antagonist (MRA) remains uncertain. METHODS AND RESULTS: Results of the EMPHASIS-HF trial in patients (n = 2737) with HF and reduced EF with mild symptoms, randomized to eplerenone or placebo, were analysed with regard to the presence or occurrence of hypokalaemia (serum K(+) <4...
November 20, 2016: European Journal of Heart Failure
https://www.readbyqxmd.com/read/27866463/pharmacokinetics-distribution-and-disposition-of-esaxerenone-a-novel-highly-potent-and-selective-non-steroidal-mineralocorticoid-receptor-antagonist-in-rats-and-monkeys
#17
Makiko Yamada, Makoto Takei, Eiko Suzuki, Hideo Takakusa, Masakatsu Kotsuma, Takuo Washio, Nobuyuki Murayama, Shin-Ichi Inoue, Takashi Izumi
1. Esaxerenone (CS-3150) is a novel non-steroidal mineralocorticoid receptor antagonist. The pharmacokinetics, tissue distribution, excretion, and metabolism of esaxerenone were evaluated in rats and monkeys. 2. Following intravenous dosing of esaxerenone at 0.1 to 3 mg/kg, the total body clearance and the volume of distribution were 3.53 to 6.69 mL/min/kg and 1.47 to 2.49 L/kg, respectively in rats, and 2.79 to 3.69 mL/min/kg and 1.34 to 1.54 L/kg, respectively in monkeys. The absolute oral bioavailability was 61...
November 21, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27856806/comparative-effectiveness-of-fourth-line-anti-hypertensive-agents-in-resistant-hypertension-a-systematic-review-and-meta-analysis
#18
REVIEW
Sarah-Jo Sinnott, Laurie A Tomlinson, Adrian A Root, Rohini Mathur, Kathryn E Mansfield, Liam Smeeth, Ian J Douglas
AIM: We assessed the effectiveness of fourth-line mineralocorticoid receptor antagonists in comparison with other fourth-line anti-hypertensive agents in resistant hypertension. METHODS AND RESULTS: We systematically searched Medline, EMBASE and the Cochrane library from database inception until January 2016. We included randomised and non-randomised studies that compared mineralocorticoid receptor antagonists with other fourth-line anti-hypertensive agents in patients with resistant hypertension...
November 17, 2016: European Journal of Preventive Cardiology
https://www.readbyqxmd.com/read/27843645/safety-and-antihypertensive-effect-of-selara%C3%A2-eplerenone-results-from-a-postmarketing-surveillance-in-japan
#19
Shoko Takahashi, Megumi Hiramatsu, Shinichi Hotta, Yukie Watanabe, Osamu Suga, Yutaka Endo, Isamu Miyamori
Prospective postmarketing surveillance of Selara (eplerenone), a selective mineralocorticoid receptor antagonist, was performed to confirm its safety and efficacy for hypertension treatment in Japan. The change in blood pressure after initiation of eplerenone treatment was also examined. Patients with essential hypertension who were eplerenone-naïve were recruited regardless of the use of other antihypertensive drugs. For examination of changes in blood pressure, patients were excluded if eplerenone was contraindicated or used off-label...
2016: International Journal of Hypertension
https://www.readbyqxmd.com/read/27835038/family-matters-collaboration-and-conflict-among-the-steroid-receptors-raises-a-need-for-group-therapy
#20
Matthew J Sikora
Antiestrogen therapies targeting the function of estrogen receptor (ER) have been the cornerstone of therapy for ER+ breast cancer for decades. However, as long as these therapies have been in use, it has also been evident that response to antiestrogen therapy is not based solely on ER expression but that other factors modify breast cancer antiestrogen response. Such factors may include ER's relatives in the steroid hormone receptor (HR) family, androgen receptor (AR), progesterone receptor (PR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR)...
December 2016: Endocrinology
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