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Late sodium current

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https://www.readbyqxmd.com/read/27887776/critical-role-of-superoxide-anions-and-hydroxyl-radicals-in-hema-induced-apoptosis
#1
H Schweikl, M Godula, C Petzel, C Bolay, K A Hiller, W Buchalla
OBJECTIVE: Resin monomers such as 2-hydroxyethyl methacrylate (HEMA) induce apoptosis because of the excess formation of reactive oxygen species (ROS). The portion of ROS including superoxide anions, hydrogen peroxide or hydroxyl radicals in monomer-induced apoptosis is unknown. Here, the effectiveness of superoxide anions or hydroxyl radicals was analyzed using tempol or sodium formate as radical scavengers. METHODS: RAW264.7 mouse macrophages were exposed to HEMA (0-6-8mM) in the presence of tempol (0-0...
November 22, 2016: Dental Materials: Official Publication of the Academy of Dental Materials
https://www.readbyqxmd.com/read/27832106/the-effect-of-a-novel-highly-selective-inhibitor-of-the-sodium-calcium-exchanger-ncx-on-cardiac-arrhythmias-in-in-vitro-and-in-vivo-experiments
#2
Zsófia Kohajda, Nikolett Farkas-Morvay, Norbert Jost, Norbert Nagy, Amir Geramipour, András Horváth, Richárd S Varga, Tibor Hornyik, Claudia Corici, Károly Acsai, Balázs Horváth, János Prorok, Balázs Ördög, Szilvia Déri, Dániel Tóth, Jouko Levijoki, Piero Pollesello, Tuula Koskelainen, Leena Otsomaa, András Tóth, István Baczkó, István Leprán, Péter P Nánási, Julius Gy Papp, András Varró, László Virág
BACKGROUND: In this study the effects of a new, highly selective sodium-calcium exchanger (NCX) inhibitor, ORM-10962 were investigated on cardiac NCX current, Ca2+ transients, cell shortening and in experimental arrhythmias. The level of selectivity of the novel inhibitor on several major transmembrane ion currents (L-type Ca2+ current, major repolarizing K+ currents, late Na+ current, Na+/K+ pump current) was also determined. METHODS: Ion currents in single dog ventricular cells (cardiac myocytes; CM), and action potentials in dog cardiac multicellular preparations were recorded utilizing the whole-cell patch clamp and standard microelectrode techniques, respectively...
2016: PloS One
https://www.readbyqxmd.com/read/27829006/hyperthermia-influences-the-effects-of-sodium-channel-blocking-drugs-in-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#3
Ibrahim El-Battrawy, Siegfried Lang, Zhihan Zhao, Ibrahim Akin, Gökhan Yücel, Sophie Meister, Bence Patocskai, Michael Behnes, Boris Rudic, Erol Tülümen, Volker Liebe, Malte Tiburcy, Jennifer Dworacek, Wolfram-Hubertus Zimmermann, Jochen Utikal, Thomas Wieland, Martin Borggrefe, Xiao-Bo Zhou
INTRODUCTION: Fever can increase the susceptibility to supraventricular and ventricular arrhythmias, in which sodium channel dysfunction has been implicated. Whether fever influences the efficacy of sodium channel blocking drugs is unknown. The current study was designed to investigate the temperature dependent effects of distinct sodium channel blocking drugs on the sodium currents in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: hiPSC-CMs were generated from human skin fibroblasts of a healthy donor...
2016: PloS One
https://www.readbyqxmd.com/read/27806966/contrasting-nav1-8-activity-in-scn10a-ventricular-myocytes-and-the-intact-heart
#4
Dina Myers Stroud, Tao Yang, Kevin Bersell, Dymtro O Kryshtal, Satomi Nagao, Christian Shaffer, Laura Short, Lynn Hall, Thomas C Atack, Wei Zhang, Bjorn C Knollmann, Franz Baudenbacher, Dan M Roden
BACKGROUND: Genome-wide association studies have implicated variants in SCN10A, which encodes Nav1.8, as modulators of cardiac conduction. Follow-up work has indicated the SCN10A sequence includes an intronic enhancer for SCN5A. Yet the role of the Nav1.8 protein in the myocardium itself is still unclear. To investigate this, we use homozygous knockout mice (Scn10a(-/-)) generated by disruption of exons 4 and 5, leaving the Scn5a enhancer intact. METHODS AND RESULTS: We previously reported that pharmacologic blockade of Nav1...
November 2, 2016: Journal of the American Heart Association
https://www.readbyqxmd.com/read/27793852/acute-exposure-to-progesterone-attenuates-cardiac-contraction-by-modifying-myofilament-calcium-sensitivity-in-the-female-mouse-heart
#5
Hirad A Feridooni, Jennifer K MacDonald, Anjali Ghimire, W Glen Pyle, Susan E Howlett
Acute application of progesterone attenuates cardiac contraction, although the underlying mechanisms are unclear. We investigated whether progesterone modified contraction in isolated ventricular myocytes and identified the Ca(2+) handling mechanisms involved in female C57BL/6 mice (6-9 mos; sodium pentobarbital anesthesia). Cells were field-stimulated (4 Hz; 37°C) and exposed to progesterone (0.001-10.0 μM) or vehicle (35 mins). Ca(2+) transients (fura-2) and cell shortening were recorded simultaneously...
October 28, 2016: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/27777148/eleclazine-an-inhibitor-of-the-cardiac-late-sodium-current-is-superior-to-flecainide-in-suppressing-catecholamine-induced-ventricular-tachycardia-and-t-wave-alternans-in-an-intact-porcine-model
#6
Danilo Bacic, Juliana Saran Carneiro, Afonso Alves Bento, Bruce D Nearing, Sridharan Rajamani, Luiz Belardinelli, Richard L Verrier
BACKGROUND: The capacity of catecholamines to induce ventricular tachycardia (VT) is well documented. OBJECTIVE: The effectiveness of the novel cardiac late sodium inhibitor eleclazine in suppressing catecholamine-induced VT in a large animal model was compared with that of flecainide. METHODS: In 13 closed-chest anesthetized Yorkshire pigs, spontaneous VT and surges in T-wave alternans (TWA) level measured using the modified moving average method were induced by epinephrine (2...
October 21, 2016: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/27733495/ranolazine-for-congenital-long-qt-syndrome-type-iii-experimental-and-long-term-clinical-data
#7
Ehud Chorin, Dan Hu, Charles Antzelevitch, Aviram Hochstadt, Luiz Belardinelli, David Zeltser, Hector Barajas-Martinez, Uri Rozovski, Raphael Rosso, Arnon Adler, Jesaia Benhorin, Sami Viskin
BACKGROUND: The basic defect in long-QT syndrome type III (LQT3) is an excessive inflow of sodium current during phase 3 of the action potential caused by mutations in the SCN5A gene. Most sodium channel blockers reduce the early (peak) and late components of the sodium current (INa and INaL), but ranolazine preferentially reduces INaL. We, therefore, evaluated the effects of ranolazine in LQT3 caused by the D1790G mutation in SCN5A. METHODS AND RESULTS: We performed an experimental study of ranolazine in TSA201 cells expressing the D1790G mutation...
October 2016: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/27713141/fibroblast-growth-factor-23-dysregulates-late-sodium-current-and-calcium-homeostasis-with-enhanced-arrhythmogenesis-in-pulmonary-vein-cardiomyocytes
#8
Shih-Yu Huang, Yao-Chang Chen, Yu-Hsun Kao, Ming-Hsiung Hsieh, Yung-Kuo Lin, Cheng-Chih Chung, Ting-I Lee, Wen-Chin Tsai, Shih-Ann Chen, Yi-Jen Chen
Fibroblast growth factor 23 (FGF23), elevated in chronic renal failure, increases atrial arrhythmogenesis and dysregulates calcium homeostasis. Late sodium currents (INa-Late) critically induces ectopic activity of pulmoanry vein (the most important atrial fibrillation trigger). This study was to investigate whether FGF23 activates the INa-Late leading to calcium dysregulation and increases PV arrhythmogenesis. Patch clamp, western blot, and confocal microscopy were used to evaluate the electrical activities, calcium homeostasis, and mitochondrial reactive oxygen species (ROS) in PV cardiomyocytes with or without FGF23 (0...
October 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27702859/antiarrhythmic-effect-of-vernakalant-in-an-experimental-model-of-long-qt-syndrome
#9
Gerrit Frommeyer, Catharina Clauss, Christian Ellermann, Harilaos Bogossian, Dirk G Dechering, Simon Kochhäuser, Florian Reinke, Christian Pott, Lars Eckardt
AIMS: The antiarrhythmic drug vernakalant exerts antiarrhythmic effects in atrial fibrillation. Recent experimental data suggest interactions with the late sodium current and antiarrhythmic effects in ventricular arrhythmias. We aimed at investigating whether treatment with vernakalant reduces polymorphic ventricular tachycardia (VT) in an experimental model of Long-QT-syndrome (LQTS). METHODS AND RESULTS: Twenty-nine isolated rabbit hearts were assigned to two groups and treated with erythromycin (300 µM, n = 15) or veratridine (0...
October 4, 2016: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
https://www.readbyqxmd.com/read/27701120/comprehensive-translational-assessment-of-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-for-evaluating-drug-induced-arrhythmias
#10
Ksenia Blinova, Jayna Stohlman, Jose Vicente, Dulciana Chan, Lars Johannesen, Maria P Hortigon-Vinagre, Victor Zamora, Godfrey Smith, William J Crumb, Li Pang, Beverly Lyn-Cook, James Ross, Mathew Brock, Stacie Chvatal, Daniel Millard, Loriano Galeotti, Norman Stockbridge, David G Strauss
BACKGROUND: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the Comprehensive in Vitro Proarrhythmia Assay (CiPA). METHODS AND RESULTS: We studied the effects of 26 drugs and 3 drug combinations on two commercially available iPSC-CM types using high-throughput voltage-sensitive dye (VSD) and microelectrode-array (MEA) assays being studied for the Comprehensive in Vitro Proarrhythmia Assessment (CiPA) initiative and compared the results to clinical QT prolongation and torsade de pointes (TdP) risk...
October 3, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27690427/discovery-of-dihydrobenzoxazepinone-gs-6615-late-sodium-current-inhibitor-late-inai-a-phase-ii-agent-with-demonstrated-preclinical-anti-ischemic-and-antiarrhythmic-properties
#11
Jeff A Zablocki, Elfatih Elzein, Xiaofen Li, Dmitry O Koltun, Eric Q Parkhill, Tetsuya Kobayashi, Ruben Martinez, Britton Corkey, Haibo Jiang, Thao Perry, Rao Kalla, Gregory T Notte, Oliver Saunders, Michael Graupe, Yafan Lu, Chandru Venkataramani, Juan Guerrero, Jason Perry, Mark Osier, Robert Strickley, Gongxin Liu, Wei-Qun Wang, Lufei Hu, Xiao-Jun Li, Nesrine El-Bizri, Ryoko Hirakawa, Kris Kahlig, Cheng Xie, Cindy Hong Li, Arvinder K Dhalla, Sridharan Rajamani, Nevena Mollova, Daniel Soohoo, Eve-Irene Lepist, Bernard Murray, Gerry Rhodes, Luiz Belardinelli, Manoj C Desai
Late sodium current (late INa) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Nav 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late INa inhibitor 1 (ranolazine)...
October 3, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27678025/emerging-drugs-to-reduce-abnormal-%C3%AE-amyloid-protein-in-alzheimer-s-disease-patients
#12
Francesco Panza, Davide Seripa, Vincenzo Solfrizzi, Bruno P Imbimbo, Madia Lozupone, Antonio Leo, Rodolfo Sardone, Gaetano Gagliardi, Lucia Lofano, Bianca C Creanza, Paola Bisceglia, Antonio Daniele, Antonello Bellomo, Antonio Greco, Giancarlo Logroscino
Currently available drugs against Alzheimer's disease (AD) target cholinergic and glutamatergic neurotransmissions without affecting the underlying disease process. Putative disease-modifying drugs are in development and target β-amyloid (Aβ) peptide and tau protein, the principal neurophatological hallmarks of the disease. Areas covered: Phase III clinical studies of emerging anti-Aβ drugs for the treatment of AD were searched in US and EU clinical trial registries and in the medical literature until May 2016...
October 6, 2016: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/27649969/epac2-rap1-signaling-regulates-reactive-oxygen-species-production-and-susceptibility-to-cardiac-arrhythmias
#13
Zhaokang Yang, Hannah Kirton, Moza Al-Owais, Jerôme Thireau, Sylvain Richard, Derek Steele, Chris Peers
AIMS: In the heart, β<sub>1</sub>-adrenergic signaling involves cyclic adenosine monophosphate (cAMP) acting via both protein kinase-A (PKA) and 'exchange protein directly activated by cAMP' (Epac): a guanine nucleotide exchange factor for the small GTPase Rap1. Inhibition of Epac-Rap1 signaling has been proposed as a therapeutic strategy for both cancer and cardiovascular disease. However, previous work suggests that impaired Rap1 signaling may have detrimental effects on cardiac function...
September 21, 2016: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/27638876/changes-in-cardiac-nav1-5-expression-function-and-acetylation-by-pan-histone-deacetylase-inhibitors
#14
Qin Xu, Dakshesh Patel, Xian Zhang, Richard D Veenstra
Histone deacetylase (HDAC) inhibitors are small molecule anticancer therapeutics that exhibit limiting cardiotoxicities including QT interval prolongation and life-threatening cardiac arrhythmias. Because the molecular mechanisms for HDAC inhibitor-induced cardiotoxicity are poorly understood, we performed whole cell patch voltage-clamp experiments to measure cardiac sodium currents (INa) from wild-type neonatal mouse ventricular or human-induced pluripotent stem cell-derived cardiomyocytes treated with trichostatin A (TSA), vorinostat (VOR), or romidepsin (FK228)...
November 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/27634981/the-role-of-18f-sodium-fluoride-pet-ct-bone-scans-in-the-diagnosis-of-metastatic-bone-disease-from-breast-and-prostate-cancer
#15
Randeep Kulshrestha, Sobhan Vinjamuri, Andrew England, Julie Nightingale, Peter Hogg
This article shall describe the role of (18)F-Sodium Fluoride ((18)F-NaF) PET/CT bone scanning in the staging of breast and prostate cancer. (18)F-NaF PET was initially utilised as a bone scanning agent in the 1960s and early 1970s, however its usage was restricted by the then available gamma cameras. The advent of hybrid PET/CT cameras in the late 1990s has shown a resurgence of interest in its usage and role. After a brief introduction, this paper will describe the radiopharmaceutical properties, dosimetry, pharmacokinetics, and mechanism of uptake of (18)F-NaF...
September 15, 2016: Journal of Nuclear Medicine Technology
https://www.readbyqxmd.com/read/27616994/reduced-sodium-current-in-the-lateral-ventricular-wall-induces-inferolateral-j-waves
#16
Veronique M F Meijborg, Mark Potse, Chantal E Conrath, Charly N W Belterman, Jacques M T De Bakker, Ruben Coronel
BACKGROUND: J-waves in inferolateral leads are associated with a higher risk for idiopathic ventricular fibrillation. We aimed to test potential mechanisms (depolarization or repolarization dependent) responsible for inferolateral J-waves. We hypothesized that inferolateral J-waves can be caused by regional delayed activation of myocardium that is activated late during normal conditions. METHODS: Computer simulations were performed to evaluate how J-point elevation is influenced by reducing sodium current conductivity (GNa), increasing transient outward current conductivity (Gto), or cellular uncoupling in three predefined ventricular regions (lateral, anterior, or septal)...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27591985/quest-to-identify-geochemical-risk-factors-associated-with-chronic-kidney-disease-of-unknown-etiology-ckdu-in-an-endemic-region-of-sri-lanka-a-multimedia-laboratory-analysis-of-biological-food-and-environmental-samples
#17
Keith E Levine, Jennifer Hoponick Redmon, Myles F Elledge, Kamani P Wanigasuriya, Kristin Smith, Breda Munoz, Vajira A Waduge, Roshini J Periris-John, Nalini Sathiakumar, James M Harrington, Donna S Womack, Rajitha Wickremasinghe
The emergence of a new form of chronic kidney disease of unknown etiology (CKDu) in Sri Lanka's North Central Province (NCP) has become a catastrophic health crisis. CKDu is characterized as slowly progressing, irreversible, and asymptomatic until late stages and, importantly, not attributed to diabetes, hypertension, or other known risk factors. It is postulated that the etiology of CKDu is multifactorial, involving genetic predisposition, nutritional and dehydration status, exposure to one or more environmental nephrotoxins, and lifestyle factors...
December 0: Environmental Monitoring and Assessment
https://www.readbyqxmd.com/read/27586294/cardiac-sodium-channel-mutations-why-so-many-phenotypes
#18
M Liu, K-C Yang, S C Dudley
The cardiac Na(+) channel (Nav1.5) conducts a depolarizing inward Na(+) current that is responsible for the generation of the upstroke Phase 0 of the action potential. In heart tissue, changes in Na(+) currents can affect conduction velocity and impulse propagation. The cardiac Nav1.5 is also involved in determination of the action potential duration, since some channels may reopen during the plateau phase, generating a persistent or late inward current. Mutations of cardiac Nav1.5 can induce gain or loss of channel function because of an increased late current or a decrease of peak current, respectively...
2016: Current Topics in Membranes
https://www.readbyqxmd.com/read/27571932/b-type-natriuretic-peptide-modulates-pulmonary-vein-arrhythmogenesis-a-novel-potential-contributor-to-the-genesis-of-atrial-tachyarrhythmia-in-heart-failure
#19
Yung-Kuo Lin, Yao-Chang Chen, Yi-Ann Chen, Yung-Hsin Yeh, Shih-Ann Chen, Yi-Jen Chen
BACKGROUND: Heart failure (HF) plays a critical role in the genesis of atrial fibrillation (AF). A high B-type natriuretic peptide (BNP) level occurs in patients with HF and in patients with AF. However, the role of BNP in the pathophysiology of AF is not clear. The purposes of this study were to evaluate the effects of BNP on pulmonary vein (PV) arrhythmogenesis. METHODS AND RESULTS: Whole-cell patch clamp and fluorescence were used to study the action potential, ionic currents, and calcium homeostasis in isolated single rabbit PV cardiomyocytes before and after a BNP infusion, with or without ODQ (10 μM), milrinone (50 μM), or ouabain (1 μM)...
August 30, 2016: Journal of Cardiovascular Electrophysiology
https://www.readbyqxmd.com/read/27569391/tolterodine-reduces-veratridine-augmented-late-ina-reverse-incx-and-early-afterdepolarizations-in-isolated-rabbit-ventricular-myocytes
#20
Chao Wang, Lei-Lei Wang, Chi Zhang, Zhen-Zhen Cao, An-Tao Luo, Pei-Hua Zhang, Xin-Rong Fan, Ji-Hua Ma
AIM: The augmentation of late sodium current (INa.L) not only causes intracellular Na(+) accumulation, which results in intracellular Ca(2+) overload via the reverse mode of the Na(+)/Ca(2+) exchange current (reverse-INCX), but also prolongs APD and induces early afterdepolarizations (EAD), which can lead to arrhythmia and cardiac dysfunction. Thus, the inhibition of INa.L is considered to be a potential way for therapeutic intervention in ischemia and heart failure. In this study we investigated the effects of tolterodine (Tol), a competitive muscarinic receptor antagonist, on normal and veratridine (Ver)-augmented INa...
November 2016: Acta Pharmacologica Sinica
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