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Late sodium current

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https://www.readbyqxmd.com/read/28109921/coronary-artery-pet-mr-imaging-feasibility-limitations-and-solutions
#1
Philip M Robson, Marc R Dweck, Maria Giovanna Trivieri, Ronan Abgral, Nicolas A Karakatsanis, Johanna Contreras, Umesh Gidwani, Jagat P Narula, Valentin Fuster, Jason C Kovacic, Zahi A Fayad
OBJECTIVES: The aims of this study were to describe the authors' initial experience with combined coronary artery positron emission tomographic (PET) and magnetic resonance (MR) imaging using (18)F-fluorodeoxyglucose ((18)F-FDG) and (18)F-sodium fluoride ((18)F-NaF) radiotracers, describe common problems and their solutions, and demonstrate the feasibility of coronary PET/MR imaging in appropriate patients. BACKGROUND: Recently, PET imaging has been applied to the aortic valve and regions of atherosclerosis...
January 13, 2017: JACC. Cardiovascular Imaging
https://www.readbyqxmd.com/read/28101642/late-sodium-current-and-intracellular-ionic-homeostasis-in-acute-ischemia
#2
Carlotta Ronchi, Eleonora Torre, Riccardo Rizzetto, Joyce Bernardi, Marcella Rocchetti, Antonio Zaza
Blockade of the late Na(+) current (I NaL) protects from ischemia/reperfusion damage; nevertheless, information on changes in I NaL during acute ischemia and their effect on intracellular milieu is missing. I NaL, cytosolic Na(+) and Ca(2+) activities (Nacyt, Cacyt) were measured in isolated rat ventricular myocytes during 7 min of simulated ischemia (ISC); in all the conditions tested, effects consistently exerted by ranolazine (RAN) and tetrodotoxin (TTX) were interpreted as due to I NaL blockade. The results indicate that I NaL was enhanced during ISC in spite of changes in action potential (AP) contour; I NaL significantly contributed to Nacyt rise, but only marginally to Cacyt rise...
March 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28045761/the-selective-late-sodium-current-inhibitor-eleclazine-unlike-amiodarone-does-not-alter-defibrillation-threshold-or-dominant-frequency-of-ventricular-fibrillation
#3
Ana F G Silva, Rodolfo Bonatti, Julio Batatinha, Bruce D Nearing, Dewan Zeng, Luiz Belardinelli, Richard L Verrier
INTRODUCTION: We examined effects of the selective late INa inhibitor eleclazine on the 50% probability of successful defibrillation (DFT50) before and after administration of amiodarone to determine its suitability for use in patients with implantable cardioverter-defibrillators (ICDs). METHODS AND RESULTS: In 20 anesthetized pigs, transvenous active-fixation cardiac defibrillation leads were fluoroscopically positioned into right ventricular apex via jugular vein...
December 28, 2016: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28025803/metabolic-transition-of-milk-lactose-synthesis-and-up-regulation-by-akt1-in-sows-from-late-pregnancy-to-lactation
#4
Fang Chen, Baoliang Chen, Wutai Guan, Jun Chen, Yantao Lv, Hanzhen Qiao, Chaoxian Wang, Yinzhi Zhang
Lactose plays a crucial role in controlling milk volume by inducing water toward into the mammary secretory vesicles from the mammary epithelial cell cytoplasm, thereby maintaining osmolality. In current study, we determined the expression of several lactose synthesis related genes, including glucose transporters (glucose transporter 1, glucose transporter 8, sodium-glucose cotransporter 1, sodium-glucose cotransporter 3, and sodium-glucose cotransporter 5), lactose synthases (α-lactalbumin and β1,4-galactosyltransferase), and hexokinases (hexokinase-1 and hexokinase-2) in sow mammary gland tissue at day 17 before delivery, on the 1st day of lactation and at peak lactation...
December 26, 2016: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28024908/hyp-17-a-novel-voltage-gated-sodium-channel-blocker-relieves-inflammatory-and-neuropathic-pain-in-rats
#5
Jee Youn Lee, Yoo Lim Kam, Jungae Oh, Dong Hyun Kim, Jin-Sung Choi, Hae Young Choi, Sungmin Han, Inchan Youn, Hea-Young Park Choo, Tae Young Yune
Clinical and experimental studies suggest that voltage-gated sodium channels (VGSCs) play a key role in the pathogenesis of neuropathic pain and that blocking agents against these channels can be potentially therapeutic. In the current study, we investigated whether a novel compound, (-)-2-Amino-1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-propan-1-one(HYP-17), binds to VGSCs and evaluated its inhibitory effect on Na(+) currents of the rat dorsal root ganglia (DRG) sensory neurons and its analgesic effect on inflammatory and neuropathic pain...
December 24, 2016: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28004395/myocardial-tissue-deformation-is-reduced-in-subjects-with-coronary-microvascular-dysfunction-but-not-rescued-by-treatment-with-ranolazine
#6
Michael D Nelson, Behzad Sharif, Jaime L Shaw, Galen Cook-Wiens, Janet Wei, Chrisandra Shufelt, Puja K Mehta, Louise E J Thomson, Daniel S Berman, Richard B Thompson, Eileen M Handberg, Carl J Pepine, Debiao Li, C Noel Bairey Merz
BACKGROUND: Patients with coronary microvascular dysfunction (CMD) often have diastolic dysfunction, representing an important therapeutic target. Ranolazine-a late sodium current inhibitor-improves diastolic function in animal models and subjects with obstructive coronary artery disease (CAD). HYPOTHESIS: We hypothesized that ranolazine would beneficially alter diastolic function in CMD. METHODS: To test this hypothesis, we performed retrospective tissue tracking analysis to evaluate systolic/diastolic strain, using cardiac magnetic resonance imaging cine images acquired in a recently completed, randomized, double-blind, placebo-controlled, crossover trial of short-term ranolazine in subjects with CMD and from 43 healthy reference controls...
December 22, 2016: Clinical Cardiology
https://www.readbyqxmd.com/read/27915058/larger-rate-dependence-of-late-sodium-current-in-cardiac-purkinje-cells-a-potential-link-to-arrhythmogenesis
#7
Wei Li, Ying Yu, Jian-Wen Hou, Zhi-Wen Zhou, Kai Guo, Peng-Pai Zhang, Zhi-Quan Wang, Jian-Hua Yan, Jian Sun, Qing Zhou, Yue-Peng Wang, Yi-Gang Li
BACKGROUND: Purkinje cells (PCs) have a steeper rate dependence of repolarization and are more susceptible to arrhythmic activity than do ventricular myocytes (VMs). Late sodium current (INaL) is rate dependent and contributes to rate dependence of repolarization. OBJECTIVE: This study sought to test our hypothesis that PCs have a larger rate dependence of INaL, contributing to their steeper rate dependence of repolarization and higher susceptibility to arrhythmic activity, than do VMs...
December 1, 2016: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/27887776/critical-role-of-superoxide-anions-and-hydroxyl-radicals-in-hema-induced-apoptosis
#8
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
#9
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
#10
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
#11
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
#12
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 mo; sodium pentobarbital anesthesia). Cells were field-stimulated (4 Hz; 37°C) and exposed to progesterone (0.001-10.0 μM) or vehicle (35 min). Ca(2+) transients (fura-2) and cell shortening were recorded simultaneously...
January 1, 2017: 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
#13
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
#14
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
#15
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
#16
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
#17
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
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). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk...
January 2017: 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
#18
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
#19
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...
December 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
#20
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
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