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Late sodium current

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https://www.readbyqxmd.com/read/29674667/a-mixed-periodic-paralysis-myotonia-mutant-p1158s-imparts-ph-sensitivity-in-skeletal-muscle-voltage-gated-sodium-channels
#1
Mohammad-Reza Ghovanloo, Mena Abdelsayed, Colin H Peters, Peter C Ruben
Skeletal muscle channelopathies, many of which are inherited as autosomal dominant mutations, include myotonia and periodic paralysis. Myotonia is defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis, known as hypokalemic periodic paralysis (hypoPP), is associated with low potassium levels. Interestingly, the P1158S missense mutant, located in the third domain S4-S5 linker of the "skeletal muscle", Nav1...
April 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29617054/activation-of-voltage-gated-sodium-current-and-inhibition-of-erg-mediated-potassium-current-caused-by-telmisartan-an-antagonist-of-angiotensin-ii-type-1-receptor-in-hl-1-atrial-cardiomyocytes
#2
Wei-Ting Chang, Sheng-Nan Wu
Telmisartan (TEL) is a non-peptide blocker of angiotensin II type-1 (AT1 ) receptor. However, the mechanisms through which this drug interacts directly with ion currents in hearts remain largely unclear. Herein, we aim to investigate the effects of TEL the on ionic currents and membrane potential of murine HL-1 cardiomyocytes. In whole-cell recordings, addition of TEL stimulated the peak and late components of voltage-gated Na+ currents (IN a ) with different potencies. The EC50 values required to achieve the stimulatory effect of this drug on peak and late IN a were 0...
April 4, 2018: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/29582428/selective-late-sodium-current-inhibitor-gs-458967-suppresses-torsades-de-pointes-by-mostly-affecting-perpetuation-but-not-initiation-of-the-arrhythmia
#3
Alexandre Bossu, Marien J C Houtman, Veronique M F Meijborg, Rosanne Varkevisser, Henriette D M Beekman, Albert Dunnink, Jacques M T de Bakker, Nevena Mollova, Sridharan Rajamani, Luiz Belardinelli, Marcel A G van der Heyden, Marc A Vos
BACKGROUND AND PURPOSE: Enhanced late sodium current (late INa ) in heart failure and long QT syndrome type 3 is proarrhythmic. GS-458967 (GS967) is a selective and potent late INa inhibitor. This study aimed to evaluate the antiarrhythmic effect of late INa inhibition by GS967 in the chronic atrioventricular block (CAVB) dog model sensitive to Torsade de Pointes arrhythmias (TdP) and to elucidate its electrophysiological mode of action in vivo and in vitro. METHODS - RESULTS: GS967 (IC50 for late INa ~ 200 nM) markedly shortened action potential duration of canine ventricular cardiomyocytes and repolarization parameters in vivo in sinus rhythm (SR, n=10) dogs, in a concentration-dependent manner...
March 27, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29579779/late-sodium-current-inhibitors-to-treat-exercise-induced-obstruction-in-hypertrophic-cardiomyopathy-an-in-vitro-study-in-human-myocardium
#4
Cecilia Ferrantini, Josè Manuel Pioner, Luca Mazzoni, Francesca Gentile, Benedetta Tosi, Alessandra Rossi, Luiz Belardinelli, Chiara Tesi, Chiara Palandri, Rosanna Matucci, Elisabetta Cerbai, Iacopo Olivotto, Corrado Poggesi, Alessandro Mugelli, Raffaele Coppini
BACKGROUND AND PURPOSE: In 30-40% of hypertrophic cardiomyopathy (HCM) patients, symptomatic left-ventricular (LV) outflow gradients develop only during exercise due to catecholamine-induced LV-hypercontractility (inducible obstruction). Negative-inotropic pharmacological options are limited to β-blockers or disopyramide, with scarce efficacy and tolerability. We assessed the potential use of late Na+ -current (INaL )-inhibitors to treat inducible obstruction in HCM. EXPERIMENTAL APPROACH: The electrophysiological and mechanical responses to β-adrenergic stimulation were studied in human myocardium from HCM versus control patients...
March 26, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29563327/inhibition-of-the-%C3%AE-subunit-of-phosphoinositide-3-kinase-pi3k-in-heart-increases-late-sodium-current-and-is-arrhythmogenic
#5
Tao Yang, David F Meoli, Javid Moslehi, Dan M Roden
While inhibition of phosphoinositide 3-kinase (PI3K) is an emerging strategy in cancer therapy, we and others have reported that this action can also contribute to drug-induced Q-T prolongation and arrhythmias by increasing cardiac late sodium current (INaL). Previous studies in mice implicate the PI3K-α isoform as the major effector of the INaL action. Here, we have determined the effects of new anticancer drugs targeting specific PI3K isoforms on INaL and action potentials (APs) in mouse cardiomyocytes and CHO cells...
March 21, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29540853/the-voltage-gated-sodium-channel-ef-hands-form-an-interaction-with-the-iii-iv-linker-that-is-disturbed-by-disease-causing-mutations
#6
Bernd R Gardill, Ricardo E Rivera-Acevedo, Ching-Chieh Tung, Mark Okon, Lawrence P McIntosh, Filip Van Petegem
Voltage-gated sodium channels (NaV ) are responsible for the rapid depolarization of many excitable cells. They readily inactivate, a process where currents diminish after milliseconds of channel opening. They are also targets for a multitude of disease-causing mutations, many of which have been shown to affect inactivation. A cluster of disease mutations, linked to Long-QT and Brugada syndromes, is located in a C-terminal EF-hand like domain of NaV 1.5, the predominant cardiac sodium channel isoform. Previous studies have suggested interactions with the III-IV linker, a cytosolic element directly involved in inactivation...
March 14, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29495239/-homocysteine-induces-calcium-overload-in-neonatal-rat-atrial-cells-through-activation-of-sodium-current-and-camk%C3%A2-%C3%AE
#7
L Han, Q B Dong, Y C Wei, A C Zheng, J X Li, K Hong, Y Q Wu, X S Cheng
Objective: To investigate the effect and related mechanism of homocysteine (Hcy) on calcium overload in neonatal rat atrial cells (NRICs). Methods: NRICs were assigned to 9 groups after culture for 3 days: (1) control group; (2) Hcy group (0, 50, 100, 200, 500 μmol/L for 48 hours); (3) antioxidant group (NAC, 10 μmol/L for 24 hours); (4) Hcy+NAC group (500 μmol/L Hcy for 48 hours, then treated with 10 μmol/L NAC for 24 hours); (5) calcium/calmodulin dependent protein kinase Ⅱδ (CaMKⅡδ) inhibitor group (KN-93, 3 μmol/L KN-93 for 5 hours); (6) specific sodium current inhibitor group (ELE, 1 μmol/L ELE for 5 hours); (7) Hcy+KN-93 group (500 μmol/L Hcy for 48 hours, then treated with 3 μmol/L KN-93 for 5 hours); (8) Hcy+ELE group (500 μmol/L Hcy for 48 hours, then treated with 1 μmol/L ELE for 5 hours; (9) Hcy+KN-93+ELE group (500 μmol/L Hcy for 48 hours, then treated with 3 μmol/L KN-93 and 1 μmol/L ELE for 5 hours)...
February 24, 2018: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/29483621/the-efficacy-of-ranolazine-on-e1784k-is-altered-by-temperature-and-calcium
#8
Mena Abdelsayed, Manpreet Ruprai, Peter C Ruben
E1784K is the most common mixed syndrome SCN5a mutation underpinning both Brugada syndrome type 1 (BrS1) and Long-QT syndrome type 3 (LQT3). The charge reversal mutant enhances the late sodium current (INa ) passed by the cardiac voltage-gated sodium channel (NaV 1.5), delaying cardiac repolarization. Exercise-induced triggers, like elevated temperature and cytosolic calcium, exacerbate E1784K late INa . In this study, we tested the effects of Ranolazine, the late INa blocker, on voltage-dependent and kinetic properties of E1784K at elevated temperature and cytosolic calcium...
February 26, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29463414/natural-meroterpenoids-isolated-from-the-plant-pathogenic-fungus-verticillium-albo-atrum-with-noteworthy-modification-action-against-voltage-gated-sodium-channels-of-central-neurons-of-helicoverpa-armigera
#9
Guangyan Wu, Lin Li, Bo Chen, Chuan Chen, Duqiang Luo, Bingjun He
A new meroterpenoid, named acetoxydehydroaustin A (1) and the known meroterpenoid austin (2) were isolated from the plant pathogenic fungus Verticillium albo-atrum. Their structures were established based on general spectroscopic techniques and the relative configuration of compound 1 was determined by single-crystal X-ray diffraction analysis. We first investigated and identified their significant electrophysiological effects on the gating kinetics of voltage-gated sodium channels in central neurons acutely dissociated from Helicoverpa armigera using whole-cell patch clamp technique...
January 2018: Pesticide Biochemistry and Physiology
https://www.readbyqxmd.com/read/29362862/the-development-of-an-in-vitro-pig-a-assay-in-l5178y-cells
#10
Rhiannon David, Emily Talbot, Bethany Allen, Amy Wilson, Usman Arshad, Ann Doherty
A recent flow cytometry-based in vivo mutagenicity assay involves the hemizygous phosphatidylinositol class A (Pig-a) gene. Pig-a forms the catalytic subunit of N-acetylglucosaminyltransferase required for glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in Pig-a prevent GPI-anchor synthesis resulting in loss of cell-surface GPI-linked proteins. The aim of the current study was to develop and validate an in vitro Pig-a assay in L5178Y mouse lymphoma cells. Ethyl methanesulfonate (EMS)-treated cells (186...
April 2018: Archives of Toxicology
https://www.readbyqxmd.com/read/29357519/enhanced-basal-late-sodium-current-appears-to-underlie-the-age-related-prolongation-of-action-potential-duration-in-guinea-pig-ventricular-myocytes
#11
Yejia Song, Luiz Belardinelli
Aging hearts have prolonged QT interval and are vulnerable to oxidative stress. Because the QT interval indirectly reflects the action potential duration (APD), we examined the hypotheses that 1) the APD of ventricular myocytes increases with age; 2) the age-related prolongation of APD is due to an enhancement of basal late Na+ current (INaL ); 3) inhibition of INaL may protect aging hearts from arrhythmogenic effects of hydrogen peroxide (H2 O2 ). Experiments were performed on ventricular myocytes isolated from one-month (young) and one-year (old) guinea pigs (GPs)...
December 14, 2017: Journal of Applied Physiology
https://www.readbyqxmd.com/read/29321131/efficacy-of-ranolazine-in-patients-with-symptomatic-hypertrophic-cardiomyopathy-the-restyle-hcm-randomized-double-blind-placebo-controlled-study
#12
Iacopo Olivotto, Paolo G Camici, Piera Angelica Merlini, Claudio Rapezzi, Monica Patten, Vicent Climent, Gianfranco Sinagra, Benedetta Tomberli, Francisco Marin, Philipp Ehlermann, Lars S Maier, Alessandra Fornaro, Claudius Jacobshagen, Antonello Ganau, Luciano Moretti, Antonio Hernandez Madrid, Raffaele Coppini, Giorgio Reggiardo, Corrado Poggesi, Francesco Fattirolli, Luiz Belardinelli, Gianfranco Gensini, Alessandro Mugelli
BACKGROUND: The late sodium current inhibitor ranolazine reverses the main electrophysiological and mechanical abnormalities of human hypertrophic cardiomyopathy (HCM) cardiomyocytes in vitro, suggesting potential clinical benefit. We aimed to assess the effect of ranolazine on functional capacity, symptomatic status, diastolic function, and arrhythmias in HCM. METHODS AND RESULTS: In this multicenter, double-blind, phase 2 study, 80 adult patients with nonobstructive HCM (age 53±14 years, 34 women) were randomly assigned to placebo (n=40) or ranolazine 1000 mg bid (n=40) for 5 months...
January 2018: Circulation. Heart Failure
https://www.readbyqxmd.com/read/29285947/eslicarbazepine-acetate-in-epilepsies-with-focal-and-secondary-generalised-seizures-systematic-review-of-current-evidence
#13
REVIEW
Laurent M Willems, Johann Philipp Zöllner, Esther Paule, Susanne Schubert-Bast, Felix Rosenow, Adam Strzelczyk
Eslicarbazepine acetate (ESL) is a third-generation antiepileptic drug (AED) approved for adjunctive treatment in adults, children, and adolescents with focal-onset seizures. Recently ESL was approved for initial monotherapy in adults. The intention of this article is to review current evidence for ESL and to summarise its pharmacological profile in comparison to other AEDs of the dibenzazepine group. Areas covered: We performed a systematic literature search in electronic databases (MEDLINE database, Cochrane Central Register of Controlled Trials, Excerpta Medica dataBASE) using a combined search strategy including the following keywords: eslicarbazepine, epilepsy and seizure...
March 2018: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/29243206/i-cal-and-i-to-mediate-rate-dependent-repolarization-in-rabbit-atrial-myocytes
#14
Jian-Wen Hou, Wei Li, Yu-Dong Fei, Yi-He Chen, Qian Wang, Yue-Peng Wang, Yi-Gang Li
Rate-dependent repolarization (RDR) of action potential (AP) in cardiomyocyte plays a critical role in the genesis of arrhythmias and RDR in atrium has been linked with atrial fibrillation. However, detailed studies focusing on the role of RDR in rabbit atrium are scant. In this study, atrial cells were isolated from rabbit heart and rate-dependent property was explored in single atrial cell to elucidate the underlying mechanism. Our results indicated that rate-dependent prolongation was evident at the action potential duration at 20% (APD20) and 50% (APD50) repolarization but not at 90% repolarization (APD90) under control condition...
February 2018: Journal of Physiology and Biochemistry
https://www.readbyqxmd.com/read/29222390/sodium-channel-remodeling-in-subcellular-microdomains-of-murine-failing-cardiomyocytes
#15
Mathilde R Rivaud, Esperanza Agullo-Pascual, Xianming Lin, Alejandra Leo-Macias, Mingliang Zhang, Eli Rothenberg, Connie R Bezzina, Mario Delmar, Carol Ann Remme
BACKGROUND: Cardiac sodium channel (NaV1.5) dysfunction contributes to arrhythmogenesis during pathophysiological conditions. Nav1.5 localizes to distinct subcellular microdomains within the cardiomyocyte, where it associates with region-specific proteins, yielding complexes whose function is location specific. We herein investigated sodium channel remodeling within distinct cardiomyocyte microdomains during heart failure. METHODS AND RESULTS: Mice were subjected to 6 weeks of transverse aortic constriction (TAC; n=32) to induce heart failure...
December 8, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29193076/resurgent-sodium-current-promotes-action-potential-firing-in-the-avian-auditory-brainstem
#16
Hui Hong, Ting Lu, Xiaoyu Wang, Yuan Wang, Jason Tait Sanchez
KEY POINTS: Auditory brainstem neurons of all vertebrates fire phase-locked action potentials (APs) at high rates with remarkable fidelity, a process controlled by specialized anatomical and biophysical properties. This is especially true in the avian nucleus magnocellularis (NM) - the analogue of the mammalian anteroventral cochlear nucleus. In addition to high voltage-activated potassium (KHVA ) channels, we report, using whole cell physiology and modelling, that resurgent sodium current (INaR ) of sodium channels (NaV ) is equally important and operates synergistically with KHVA channels to enable rapid AP firing in NM...
February 1, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29177922/sglt1-and-sglt1-inhibitors-a-role-to-be-assessed-in-the-current-clinical-practice
#17
Leonardo Spatola, Silvia Finazzi, Claudio Angelini, Marco Dauriz, Salvatore Badalamenti
Diabetes is a complex disease of increasingly common occurrence worldwide. Attaining optimal glycemic control is the main challenge to prevent the development of diabetes-related complications and/or to stop their progression. In recent years, the pharmacologic toolkit for the treatment of diabetes has considerably expanded, thus paving the way to more pathophysiology-oriented therapies. For instance, the sodium-glucose cotransporters SGLT2 and SGLT1 have been in the spotlight because of better knowledge of their physiology and therapeutic potential...
February 2018: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
https://www.readbyqxmd.com/read/29139614/human-dental-stem-cell-derived-transgene-free-ipscs-generate-functional-neurons-via-embryoid-body-mediated-and-direct-induction-methods
#18
Ikbale El Ayachi, Jun Zhang, Xiao-Ying Zou, Zongdong Yu, Wei Wei, Kristen M S O'Connell, George T-J Huang
Induced pluripotent stem cells (iPSCs) give rise to neural stem/progenitor cells (NSCs), serving as a good source for neural regeneration. Here, we established transgene-free (TF) iPSCs from dental stem cells (DSCs) and determined their capacity to differentiate into functional neurons in vitro. Generated TF iPSCs from stem cells of apical papilla (SCAP) and dental pulp stem cells (DPSCs) underwent two methods -- embryoid body (EB)-mediated and direct induction, to guide TF-DSC iPSCs along with H9 or H9 Syn-GFP (human embryonic stem cells) into functional neurons in vitro...
November 15, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/29130489/angiotensin-1-7-modulates-electrophysiological-characteristics-and-calcium-homoeostasis-in-pulmonary-veins-cardiomyocytes-via-mas-pi3k-enos-signalling-pathway
#19
Yen-Yu Lu, Wen-Shiann Wu, Yung-Kuo Lin, Chen-Chuan Cheng, Yao-Chang Chen, Shih-Ann Chen, Yi-Jen Chen
BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia, and pulmonary veins (PVs) play a critical role in triggering AF. Angiotensin (Ang)-(1-7) regulates calcium (Ca2+ ) homoeostasis and also plays a critical role in cardiovascular pathophysiology. However, the role of Ang-(1-7) in PV arrhythmogenesis remains unclear. MATERIALS AND METHODS: Conventional microelectrodes, whole-cell patch-clamp and the fluo-3 fluorimetric ratio technique were used to record ionic currents and intracellular Ca2+ in isolated rabbit PV preparations and in single isolated PV cardiomyocytes, before and after administration of Ang-(1-7)...
January 2018: European Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29127493/late-sodium-current-associated-cardiac-electrophysiological-and-mechanical-dysfunction
#20
REVIEW
Shandong Yu, Gang Li, Christopher L-H Huang, Ming Lei, Lin Wu
Late sodium current (INaL ) is a small sustained inward current observed during the cardiac action potential plateau phase following decay of the early peak INa . The endogenous INaL is relatively small in normal hearts but exerts functionally significant effects on cardiomyocyte repolarization with potentially pro-arrhythmic effects in hearts with reduced repolarization reserve. Enhanced INa,L occurs in long QT syndrome 3 (LQTS 3) patients, and under a number of pathological and pharmacological cardiovascular conditions, including bradycardia, myocardial ischemia, reperfusion injury, and heart failure...
March 2018: Pflügers Archiv: European Journal of Physiology
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