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https://www.readbyqxmd.com/read/29042083/aprotinin-prevents-proteolytic-epithelial-sodium-channel-enac-activation-and-volume-retention-in-nephrotic-syndrome
#1
Bernhard N Bohnert, Martina Menacher, Andrea Janessa, Matthias Wörn, Anja Schork, Sophie Daiminger, Hubert Kalbacher, Hans-Ulrich Häring, Christoph Daniel, Kerstin Amann, Florian Sure, Marko Bertog, Silke Haerteis, Christoph Korbmacher, Ferruh Artunc
Volume retention in nephrotic syndrome has been linked to activation of the epithelial sodium channel (ENaC) by proteolysis of its γ-subunit following urinary excretion of serine proteases such as plasmin. Here we tested whether pharmacological inhibition of urinary serine protease activity might protect from ENaC activation and volume retention in nephrotic syndrome. Urine from both nephrotic mice (induced by doxorubicin injection) and nephrotic patients exhibited high aprotinin-sensitive serine protease activity...
October 14, 2017: Kidney International
https://www.readbyqxmd.com/read/29036504/echocardiographic-left-ventricular-reverse-remodeling%C3%A2-after-18-months-of-antihypertensive-treatment-in-stage-i-hypertension-results-from-the-prever-treatment-study
#2
C Bertoluci, M Foppa, A B S Santos, T V Branchi, S C Fuchs, F D Fuchs
Background: Antihypertensive treatment improves echocardiographic parameters of hypertensive target organ damage in stage II hypertension, but less is known about the effects in stage I hypertension. Methods: In a cohort study nested in the randomized double-blind trial PREVER-treatment, two-dimensional echocardiograms were performed in 110 individuals, aged 54.8 ± 7.9 years-old, with stage I hypertension at baseline and after 18 months of treatment with chlorthalidone/amiloride or losartan...
September 27, 2017: American Journal of Hypertension
https://www.readbyqxmd.com/read/29032204/angtensin-ii-elicits-a-camp-dependent-intestinal-anion-secretion-by-stimulating-pge2-release-through-at1-subtype-receptors-in-rat-ileum
#3
Ling Xiao, Hong-Wei Liu, Hong Di, Li-Xin Chen, Qing Zhou, Xin Yu, Haiyan Jing, Shuhai Tang
A growing literature has demonstrated that the renin-angiotensin system (RAS) involves in gut function. Angiotensin II (AngII) stimulates Cl(-) secretion in intestine epithelial cells. However, the underlying signal pathway remains unexplored. Here, we explored that serosal application of Ang II (5 × 10(-8) M) significantly increased the baseline Isc compared to the control group in rat ileum. Tetrodotoxin (TTX) failed to suppress Isc evoked by Ang II. However, the Ang II-evoked Isc was significantly suppressed by the ATR1 antagonist losartan instead of ATR2 antagonist PD123319...
October 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29026553/gitelman-syndrome-a-rare-life-threatening-case-of-hypokalemic-paralysis-mimicking-guillain-barr%C3%A3-syndrome-during-pregnancy-and-review-of-the-literature
#4
Abdelghafour Elkoundi, Noureddine Kartite, Mustapha Bensghir, Nawfal Doghmi, Salim Jaafar Lalaoui
In rare cases, patients with Gitelman syndrome may present with hypokalemic paralysis mimicking Guillain-Barré syndrome. The severity of resultant symptoms may be life-threatening. Controversial drugs such as aldactone, amiloride, and eplerenone should be used in this situation despite the lack of safety data.
October 2017: Clinical Case Reports
https://www.readbyqxmd.com/read/29025967/diminazene-is-a-slow-pore-blocker-of-acid-sensing-ion-channel-1a-asic1a
#5
Axel Schmidt, Giulia Rossetti, Sylvia Joussen, Stefan Grunder
Acid-sensing ion channels (ASICs) are neuronal receptors for extracellular protons. They contribute to the excitatory postsynaptic current and to the detection of painful acidosis. Moreover, they are activated during peripheral inflammation and acidosis associated with various neuronal disorders such as stroke and neuro-inflammation, rendering them interesting drug targets. Diminazene aceturate is a small molecule inhibitor of ASICs with a reported apparent affinity in the low micromolar range, making it an interesting lead compound...
October 12, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28984146/nonclinical-safety-assessment-of-spx-101-a-novel-peptide-promoter-of-epithelial-sodium-channel-internalization-for-the-treatment-of-cystic-fibrosis
#6
Matthew P Walker, Matt Cowlen, Dale Christensen, Mutsumi Miyamoto, Phillip Barley, Timothy Crowder
BACKGROUND: ENaC inhibition has long been an attractive therapeutic target for the treatment of cystic fibrosis. However, previous attempts at developing ENaC inhibitors have been unsuccessful due to complications arising from systemic circulation of the compounds. Here, we describe the preclinical toxicology assessment of a new inhaled peptide promoter of ENaC internalization delivered as a nebulized aerosol. METHODS: Preclinical assessment of SPX-101 safety was determined using an in vitro hERG assay, bolus injection of SPX-101 in a canine cardiovascular and respiratory safety pharmacology model and 28-day inhalation toxicology studies of nebulized drug in rats and dogs...
October 6, 2017: Inhalation Toxicology
https://www.readbyqxmd.com/read/28982737/evaluation-of-a-splunc1-derived-peptide-for-the-treatment-of-cystic-fibrosis-lung-disease
#7
Shawn T Terryah, Robert C Fellner, Saira Ahmad, Patrick John Moore, Boris Reidel, Juliana I Sesma, Christine S Kim, Alaina L Garland, David W Scott, Juan R Sabater, Jerome Carpenter, Scott H Randell, Mehmet Kesimer, William M Abraham, William J Arendshorst, Robert Tarran
In cystic fibrosis (CF) lungs, epithelial Na+ channel (ENaC) hyperactivity causes a reduction in airway surface liquid (ASL) volume, leading to decreased mucocilliary clearance and lung damage. Inhibition of ENaC is an attractive therapeutic option. However, ENaC antagonists have failed clinically due to off-target renal effects. The S18 peptide is a naturally occurring short palate lung and nasal epithelial clone 1 (SPLUNC1)-derived ENaC antagonist that restores ASL height for up to 24 h in CF human bronchial epithelial cultures...
October 5, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28981821/sodium-carbonate-is-saltier-than-sodium-chloride-to-sodium-depleted-rats
#8
Steven J St John, Anya M McBrayer, Erin E Krauskopf
In a series of behavioral experiments in the 1960s, G.R. Morrison identified several unique features of the taste of Na2CO3 to rats; namely, it is 1) considerably more intense than NaCl at isomolar concentrations, 2) avoided at 10 times lower concentrations than NaCl to thirsty rats, 3) preferred at 10 times lower concentrations than NaCl in sodium-depleted rats. He also demonstrated its qualitatively similarity to NaCl. In Experiment 1, we confirmed and extended many of Morrison's observations. Rats were injected with furosemide on 3 occasions to stimulate a sodium appetite...
October 1, 2017: Chemical Senses
https://www.readbyqxmd.com/read/28978526/loss-of-inversin-decreases-transepithelial-sodium-transport-in-murine-renal-cells
#9
Nalini H Kulkarni, Rosamund C Smith, Bonnie L Blazer-Yost
Type II nephronophthisis (NPHP2) is an autosomal recessive renal cystic disorder characterized by mutations in the inversin gene. Humans and mice with mutations in inversin have enlarged cystic kidneys that may be due to fluid accumulation resulting from altered ion transport. To address this, transepithelial ion transport was measured in shRNA mediated inversin-depleted mouse cortical collecting duct (mCCD) cells. Loss of inversin decreased the basal ion flux in mCCD cells compared to controls. Depletion of inversin decreased vasopressin-induced Na+ absorption, but did not alter Cl- secretion by mCCD cells...
October 4, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28972182/urokinase-type-plasminogen-activator-upa-is-critical-for-progression-of-tuberous-sclerosis-complex-2-tsc2-deficient-tumors
#10
Victoria Stepanova, Konstantin V Dergilev, Kelci R Holman, Yelena V Parfyonova, Zoya I Tsokolaeva, Mimi Teter, Elena N Atochina-Vasserman, Alla Volgina, Sergei V Zaitsev, Shane P Lewis, Fedor G Zabozlaev, Kseniya Obraztsova, Vera P Krymskaya, Douglas B Cines
Lymphangioleiomyomatosis (LAM) is a fatal lung disease associated with germline or somatic inactivating mutations in tuberous sclerosis complex genes (TSC1 or TSC2). LAM is characterized by neoplastic growth of smooth muscle (SM)-α-actin-positive cells, that destroy lung parenchyma, and by the formation of benign renal neoplasms called angiolipomas. The mTOR complex 1 (mTORC1) inhibitor rapamycin slows progression of these diseases, but is not curative and associated with notable toxicity at clinically effective doses, highlighting the need for better understanding LAM's molecular etiology...
September 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28970722/pharmacological-evaluation-of-nsaid-induced-gastropathy-as-a-translatable-model-of-referred-visceral-hypersensitivity
#11
Michele Hummel, Terri Knappenberger, Meghan Reilly, Garth T Whiteside
AIM: To evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity. METHODS: Gastric ulcer pain was induced by the oral administration of indomethacin to male, CD1 mice (n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated...
September 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28967043/jet-dispensing-of-multi-layered-films-for-the-co-delivery-of-three-antihypertensive-agents
#12
Nicolaos Scoutaris, Maria Malamatari, Adrien Letellier, Dennis Douroumis
Three-layer thin films comprising of two polymers as substrate (ethyl cellulose and, copovidone K28) and three antihypertensive agents (hydrochlorothiazide, amiloride HCl, and carvedilol) were printed using jet dispensing technology. Two film formulations with different ethyl cellulose to copovidone K28 ratio (i.e., 90/10 and 50/50 w/w) were prepared using a three-course dispensing. The films were characterized regarding surface morphology, solid-state properties, polymer-drug interactions, drug distribution in each layer, and in vitro drug release...
October 2, 2017: Drug Delivery and Translational Research
https://www.readbyqxmd.com/read/28950807/durable-complete-remission-following-anti-egfr-antibodies-in-recurrent-metastatic-colorectal-cancer
#13
Etienne Boudrias-Dalle, Magali Cloutier, Marjorie Harvey, Guy Leblanc, Olivier Besner-Morin, Jean-Philippe Adam
In this case report, we describe a patient who remains in complete remission two years after the discontinuation of anti-EGFR monotherapy as a third-line treatment, accompanied by persistent severe hypomagnesemia. A 45-year-old Caucasian woman with mCRC started chemotherapy with weekly cetuximab. After ten months of treatment, the therapy was stopped because the patient had persistent grade III hypomagnesemia despite amiloride, oral, and intravenous magnesium. A month later, the patient was switched to panitumumab 6 mg/kg every two weeks for four additional months to avoid weekly visits to the clinic...
January 1, 2017: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/28920862/enhanced-endothelium-epithelial-sodium-channel-signaling-prompts-left-ventricular-diastolic-dysfunction-in-obese-female-mice
#14
Guanghong Jia, Javad Habibi, Annayya R Aroor, Michael A Hill, Vincent G DeMarco, Li E Lee, Lixin Ma, Brady J Barron, Adam Whaley-Connell, James R Sowers
OBJECTIVE: Enhanced activation of cell specific mineralocorticoid receptors (MRs) in obesity plays a key role in the development of cardiovascular disease including cardiac diastolic dysfunction as a critical prognosticator. Our previous investigations demonstrated that selective endothelium MR activation promotes a maladaptive inflammatory response and fibrosis in cardiovascular tissue in female mice fed a western diet (WD), and this was associated with expression and activation of the epithelial sodium channel on the surface of endothelial cells (EnNaC)...
September 8, 2017: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/28915228/analysis-of-the-genes-involved-in-mendelian-forms-of-low-renin-hypertension-in-chinese-early-onset-hypertensive-patients
#15
Kai Liu, Fang Qin, Xiaolu Sun, Yang Zhang, Jizheng Wang, Yajie Wu, Wenjun Ma, Wei Wang, Xueyi Wu, Ying Qin, Huimin Zhang, Xianliang Zhou, Haiying Wu, Rutai Hui, Yubao Zou, Xiongjing Jiang, Lei Song
BACKGROUND: The study aimed to analyze genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients. METHODS: A panel of nine genes, namely SCNN1B, SCNN1G, WNK1, WNK4, KLHL3, CUL3, nuclear receptor subfamily 3, group C (NR3C)1, NR3C2, and HSD11B2 were screened by targeted resequencing in 260 Chinese early-onset hypertensive patients. Additionally, exon 13 of both SCNN1B and SCNN1G was sequenced in an independent cohort of 506 Chinese early-onset hypertensive patients...
September 14, 2017: Journal of Hypertension
https://www.readbyqxmd.com/read/28905546/-hypertension-in-people-of-african-descent
#16
Fabien Cane, Sofia Zisimopoulou, Antoinette Pechère-Bertschi
Hypertension in people of African descent presents an increased prevalence, an earlier and more severe target organ damage and is harder to control compared to other ethnicities. Preeclampsia and gestational hypertension are more frequent in black women. The physiological phenomenon of night time blood pressure dipping is often blunted. The low renin hypertension phenotype seems to be caused by an increase in sodium retention at renal level. The treatment of choice is calcium channel blockers and thiazide diuretics along with a renin-angiotensin-aldosterone blocker for kidney protection...
September 13, 2017: Revue Médicale Suisse
https://www.readbyqxmd.com/read/28895869/amiloride-interferes-with-platelet-activating-factor-induced-respiratory-burst-and-mmp-9-release-in-bovine-neutrophils-independent-of-na-h-exchanger-1
#17
C S Larrazabal, M D Carretta, M A Hidalgo, R A Burgos
Cytoplasmic pH homeostasis is required for an appropriate response in polymorphonuclear neutrophils (PMNs). In these cells, chemotaxis and reactive oxygen species (ROS) production are reduced by the use of Na(+)/H(+) exchanger (NHE-1) inhibitors, but these results are mainly obtained using amiloride, a non-selective NHE-1 inhibitor. In bovine PMNs, the role of NHE-1 in functional responses has not been confirmed yet. The aim of this study was to determine the role of NHE-1 using amiloride and zoniporide in pH regulation, ROS production, matrix metalloproteinase 9 (MMP-9) release and calcium flux in bovine PMNs induced by the platelet activation factor (PAF), additionally we evaluated the presence of NHE-1 and NHE-2 mRNA Our data show the presence only of NHE-1 but not NHE-2 in bovine PMNs...
September 2017: Veterinary Immunology and Immunopathology
https://www.readbyqxmd.com/read/28890943/trial-of-amiloride-in-type-2-diabetes-with-proteinuria
#18
Mark L Unruh, V Shane Pankratz, John E Demko, Evan C Ray, Rebecca P Hughey, Thomas R Kleyman
INTRODUCTION: Renal Na(+) retention and extracellular fluid volume expansion are hallmarks of nephrotic syndrome, which occurs even in the absence of activation of hormones that stimulate renal Na(+) transporters. Plasmin-dependent activation of the epithelial Na(+) channel (ENaC) has been proposed to have a role in renal Na(+) retention in the setting of nephrotic syndrome. We hypothesized that the ENaC inhibitor amiloride would be an effective therapeutic agent in inducing a natriuresis and lowering blood pressure in individuals with macroscopic proteinuria...
September 2017: KI Reports
https://www.readbyqxmd.com/read/28877076/disruption-of-the-with-no-lysine-kinase-ste20-proline-alanine-rich-kinase-pathway-reduces-the-hypertension-induced-by-angiotensin-ii
#19
Luz G Cervantes-Perez, Maria Castaneda-Bueno, Jose V Jimenez, Norma Vazquez, Lorena Rojas-Vega, Dario R Alessi, Norma A Bobadilla, Gerardo Gamba
OBJECTIVE: The hypertensive effect of angiotensin II (AngII), a peptide hormone, is dependent on its intrarenal actions and the activation of the renal Na-Cl cotransporter (NCC), by AngII requires integrity of the with no lysine kinase/STE20-proline alanine-rich kinase (WNK/SPAK) signaling pathway. Here, we analyzed if the integrity of the WNK/SPAK pathway is required for AngII infusion to induce arterial hypertension. METHODS: We tested the effect of AngII or aldosterone administration on the blood pressure and on pNCC/NCC ratio in SPAK knock-in mice in which the kinase and thus NCC cannot be activated by WNK kinases...
September 14, 2017: Journal of Hypertension
https://www.readbyqxmd.com/read/28876128/influence-of-inhaled-amiloride-on-lung-fluid-clearance-in-response-to-normobaric-hypoxia-in-healthy-individuals
#20
Courtney M Wheatley, Sarah E Baker, Bryan J Taylor, Manda L Keller-Ross, Steven C Chase, Alex R Carlson, Robert J Wentz, Eric M Snyder, Bruce D Johnson
Wheatley, Courtney M., Sarah E. Baker, Bryan J. Taylor, Manda L. Keller-Ross, Steven C. Chase, Alex R. Carlson, Robert J. Wentz, Eric M. Snyder, and Bruce D. Johnson. Influence of inhaled amiloride on lung fluid clearance in response to normobaric hypoxia in healthy individuals. High Alt Med Biol 00:000-000, 2017. AIM: To investigate the role of epithelial sodium channels (ENaC) on lung fluid clearance in response to normobaric hypoxia, 20 healthy subjects were exposed to 15 hours of hypoxia (fraction of inspired oxygen [FiO2] = 12...
September 6, 2017: High Altitude Medicine & Biology
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