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Late sodium current

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https://www.readbyqxmd.com/read/28213505/revealing-the-concealed-nature-of-long-qt-type-3-syndrome
#1
Amara Greer-Short, Sharon A George, Steven Poelzing, Seth H Weinberg
BACKGROUND: Gain-of-function mutations in the voltage-gated sodium channel (Nav1.5) are associated with the long-QT-3 (LQT3) syndrome. Nav1.5 is densely expressed at the intercalated disk, and narrow intercellular separation can modulate cell-to-cell coupling via extracellular electric fields and depletion of local sodium ion nanodomains. Models predict that significantly decreasing intercellular cleft widths slows conduction because of reduced sodium current driving force, termed "self-attenuation...
February 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/28202629/improving-the-in-silico-assessment-of-proarrhythmia-risk-by-combining-herg-human-ether-%C3%A3-go-go-related-gene-channel-drug-binding-kinetics-and-multichannel-pharmacology
#2
Zhihua Li, Sara Dutta, Jiansong Sheng, Phu N Tran, Wendy Wu, Kelly Chang, Thembi Mdluli, David G Strauss, Thomas Colatsky
BACKGROUND: The current proarrhythmia safety testing paradigm, although highly efficient in preventing new torsadogenic drugs from entering the market, has important limitations that can restrict the development and use of valuable new therapeutics. The CiPA (Comprehensive in vitro Proarrhythmia Assay) proposes to overcome these limitations by evaluating drug effects on multiple cardiac ion channels in vitro and using these data in a predictive in silico model of the adult human ventricular myocyte...
February 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/28185917/increment-of-late-sodium-currents-in-the-left-atrial-myocytes-and-its-potential-contribution-to-the-increased-susceptibility-of-atrial-fibrillation-in-castrated-male-mice
#3
Yang Zhang, Hui-Min Wang, Ying-Zhe Wang, Yi-Yuan Zhang, Xue-Xin Jin, Yue Zhao, Jin Wang, Yi-Lin Sun, Gen-Long Xue, Peng-Hui Li, Qi-He Huang, Bao-Feng Yang, Zhen-Wei Pan
BACKGROUND: The incidence of atrial fibrillation (AF) is correlated with the declined levels of testosterone in elder men. Late sodium current may exert a role in AF pathogenesis. OBJECTIVE: In this study we explored the effect of testosterone deficiency on AF susceptibility and the therapeutic effect of late sodium current inhibitors in mice. METHODS: Male ICR mice (5-week old) were castrated to establish testosterone deficiency model. One month after castration, dihydrotestosterone (5mg/kg) was administered subcutaneously for 2 months...
February 6, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28151960/d-amino-acids-reduce-enterococcus-faecalis-biofilms-in-vitro-and-in-the-presence-of-antimicrobials-used-for-root-canal-treatment
#4
Peter S Zilm, Victor Butnejski, Giampiero Rossi-Fedele, Stephen P Kidd, Suzanne Edwards, Krasimir Vasilev
Enterococcus faecalis is the most frequent species present in post-treatment disease and plays a significant role in persistent periapical infections following root canal treatment. Its ability to persist in stressful environments is inter alia, due to its ability to form biofilms. The presence of certain D-amino acids (DAAs) has previously been shown to reduce formation of Bacillus subtilis biofilms. The aims of this investigation were to determine if DAAs disrupt biofilms in early and late growth stages for clinical E...
2017: PloS One
https://www.readbyqxmd.com/read/28148645/nonlinear-effects-of-hyperpolarizing-shifts-in-activation-of-mutant-nav1-7-channels-on-resting-membrane-potential
#5
Mark Estacion, Stephen G Waxman
The Nav1.7 sodium channel is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Gain-of-function mutations that cause the painful disorder inherited erythromelalgia (IEM) shift channel activation in a hyperpolarizing direction. When expressed within DRG neurons, these mutations produce a depolarization of resting membrane potential (RMP). The biophysical basis for the depolarized RMP has to date not been established. To explore the effect on RMP of the shift in activation associated with a prototypical IEM mutation (L858H), we used dynamic clamp models that represent graded shifts that fractionate the effect of the mutation on activation voltage-dependence...
February 1, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28125029/excavatolide-b-modulates-the-electrophysiological-characteristics-and-calcium-homeostasis-of-atrial-myocytes
#6
Hwong-Ru Hwang, Buh-Yuan Tai, Pao-Yun Cheng, Ping-Nan Chen, Ping-Jyun Sung, Zhi-Hong Wen, Chih-Hsueng Hsu
Severe bacterial infections caused by sepsis always result in profound physiological changes, including fever, hypotension, arrhythmia, necrosis of tissue, systemic multi-organ dysfunction, and finally death. The lipopolysaccharide (LPS) provokes an inflammatory response under sepsis, which may increase propensity to arrhythmogenesis. Excavatolide B (EXCB) possesses potent anti-inflammatory effects. However, it is not clear whether EXCB could modulate the electrophysiological characteristics and calcium homeostasis of atrial myocytes...
January 24, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28117139/epigallocatechin-3-gallate-modulates-arrhythmogenic-activity-and-calcium-homeostasis-of-left-atrium
#7
Jun-Hei Chang, Shih-Lin Chang, Po-Da Hong, Ping-Nan Chen, Chih-Hsueng Hsu, Yen-Yu Lu, Yao-Chang Chen
BACKGROUND: Atrial fibrillation (AF) is the commonest sustained arrhythmia, and increases the risk of stroke, heart failure, and mortality. Calcium (Ca(2+)) overload and oxidative stress are thought to participate in the pathogenesis of AF. Epigallocatechin-3-gallate (EGCG) has an antioxidative effect and been shown to be beneficial in promoting cardiovascular health. However, it is not clear if EGCG directly modulates the electrophysiological characteristics and Ca(2+) homeostasis of the left atrium (LA)...
January 14, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28109921/coronary-artery-pet-mr-imaging-feasibility-limitations-and-solutions
#8
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
#9
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
#10
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
#11
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
#12
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...
February 2017: 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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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