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https://www.readbyqxmd.com/read/29339676/electrical-and-histological-remodeling-of-the-pulmonary-vein-in-2k1c-hypertensive-rats-indication-of-initiation-and-maintenance-of-atrial-fibrillation
#1
Pan Pan Xia, Lian Jing Li, Run Di Qi, Jiao Jiao Shi, Wei Zhu Ju, Ming Long Chen
OBJECTIVE: Hypertension is a significant risk factor for atrial fibrillation (AF). The role of pulmonary vein (PV) remodeling in the mechanistic association between hypertension and AF is not definitive. In this study, we aimed to identify changes in the electrophysiology and histology in PVs in two-kidney, one-clip (2K1C) hypertensive rats. METHODS: Fifty male Sprague-Dawley rats were classified into the 2K1C and sham-operated groups. The systolic blood pressure was measured every 2 weeks...
January 17, 2018: Anatolian Journal of Cardiology
https://www.readbyqxmd.com/read/29335582/differential-roles-of-nav1-2-and-nav1-6-in-regulating-neuronal-excitability-at-febrile-temperature-and-distinct-contributions-to-febrile-seizures
#2
Mingyu Ye, Jun Yang, Cuiping Tian, Qiyu Zhu, Luping Yin, Shan Jiang, Mingpo Yang, Yousheng Shu
Dysregulation of voltage-gated sodium channels (VGSCs) is associated with multiple clinical disorders, including febrile seizures (FS). The contribution of different sodium channel subtypes to environmentally triggered seizures is not well understood. Here we demonstrate that somatic and axonal sodium channels primarily mediated through NaV1.2 and NaV1.6 subtypes, respectively, behave differentially at FT, and might play distinct roles in FS generation. In contrast to sodium channels on the main axonal trunk, somatic ones are more resistant to inactivation and display significantly augmented currents, faster gating rates and kinetics of recovery from inactivation at FT, features that promote neuronal excitabilities...
January 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29330131/response-of-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-to-several-pharmacological-agents-when-intrinsic-syncytial-pacing-is-overcome-by-acute-external-stimulation
#3
Haoyu Zeng, Bharathi Balasubramanian, Armando Lagrutta, Frederick Sannajust
We challenged human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) syncytia, mainly, CDI iCells with several classes of well-characterized pharmacological agents (including hERG blocker, Nav1.5 blocker, Cav1.2 blocker and opener, β-adrenergic agonist, and If blocker) under pacing conditions, utilizing the Cardio-ECR instrument, a non-invasive platform featuring simultaneous and continuous measurement of synchronized beating rate and contractility (both signals were acquired simultaneously and well aligned) ...
January 9, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29311306/mechanism-specific-assay-design-facilitates-the-discovery-of-nav1-7-selective-inhibitors
#4
Tania Chernov-Rogan, Tianbo Li, Gang Lu, Henry Verschoof, Kuldip Khakh, Steven W Jones, Maureen H Beresini, Chang Liu, Daniel F Ortwine, Steven J McKerrall, David H Hackos, Daniel Sutherlin, Charles J Cohen, Jun Chen
Many ion channels, including Nav1.7, Cav1.3, and Kv1.3, are linked to human pathologies and are important therapeutic targets. To develop efficacious and safe drugs, subtype-selective modulation is essential, but has been extremely difficult to achieve. We postulate that this challenge is caused by the poor assay design, and investigate the Nav1.7 membrane potential assay, one of the most extensively employed screening assays in modern drug discovery. The assay uses veratridine to activate channels, and compounds are identified based on the inhibition of veratridine-evoked activities...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29306897/critical-roles-of-xirp-proteins-in-cardiac-conduction-and-their-rare-variants-identified-in-sudden-unexplained-nocturnal-death-syndrome-and-brugada-syndrome-in-chinese-han-population
#5
Lei Huang, Kuo-Ho Wu, Liyong Zhang, Qinchuan Wang, Shuangbo Tang, Qiuping Wu, Pei-Hsiu Jiang, Jim Jung-Ching Lin, Jian Guo, Lin Wang, Shih-Hurng Loh, Jianding Cheng
BACKGROUND: Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unclear etiology. Arrhythmia has been implicated in SUNDS. Mutations/deficiencies in intercalated disc components have been shown to cause arrhythmias. Human cardiomyopathy-associated 1 (XIRP1) and 3 (XIRP2) are intercalated disc-associated, Xin repeats-containing proteins. Mouse Xirp1 is necessary for the integrity of intercalated disc and for the surface expression of transient outward and delayed rectifier K+ channels, whereas mouse Xirp2 is required for Xirp1 intercalated disc localization...
January 6, 2018: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29288034/structural-and-functional-remodelling-of-the-atrioventricular-node-with-ageing-in-rats-the-role-of-hyperpolarization-activated-cyclic-nucleotide-gated-and-ryanodine-2-channels
#6
Yawer Saeed, Ian Temple, Zoltan Borbas, Andrew Atkinson, Joseph Yanni, Michal Maczewski, Urszula Mackiewicz, Mariam Aly, Sunil J R J Logantha, Clifford Garratt, Halina Dobrzynski
BACKGROUND: Ageing is associated with an increased incidence of atrioventricular nodal (AVN) dysfunction. OBJECTIVES: The aim of the study is to identify the structural and functional remodelling in the atrioventricular junction (AVJ) with ageing. METHODS: Electrophysiological, histology and immunohistochemistry experiments on male Wistar-Hanover rats aged 3months (n=24) and 2years (n=15) were performed. AH interval, Wenkebach cycle length (WBCL) and AVN effective refractory period (AVNERP) were measured...
December 26, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/29262297/antiallodynic-and-antihyperalgesic-activity-of-new-3-3-diphenyl-propionamides-with-anticonvulsant-activity-in-models-of-pain-in-mice
#7
Anna Rapacz, Jolanta Obniska, Paulina Koczurkiewicz, Katarzyna Wójcik-Pszczoła, Agata Siwek, Anna Gryboś, Sabina Rybka, Aleksandra Karcz, Elżbieta Pękala, Barbara Filipek
Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic pain. The aim of the present experiments was to examine analgesic activity of three new 3,3-diphenyl-propionamides, which had previously demonstrated anticonvulsant activity in the MES (maximal electroshock seizure), scPTZ (subcutaneous pentylenetetrazole) and/or 6Hz (psychomotor seizure) tests in mice. Antinociceptive activity was examined in mouse models of acute pain (the hot plate test) and tonic pain (the formalin test) in mice...
December 17, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29194125/nav1-7-and-pain-contribution-of-peripheral-nerves
#8
Tal Hoffmann, Ohad Sharon, Jürgen Wittmann, Richard W Carr, Alina Vyshnevska, Roberto De, Mohammed A Nassar, Peter W Reeh, Christian Weidner
The sodium channel NaV1.7 contributes to action potential generation and propagation. Loss-of-function mutations in patients lead to congenital indifference to pain, though it remains unclear where on the way from sensory terminals to CNS the signalling is disrupted. We confirm that conditional deletion of NaV1.7 in advillin expressing sensory neurons leads to impaired heat and mechanical nociception in behavioural tests. With single-fiber recordings from isolated skin we found (1) a significantly lower prevalence of heat responsiveness to in normally mechanosensitive C-fibers, although (2) the rare heat responses appeared quite vigorous and (3) heat-induced CGRP release was normal...
November 24, 2017: Pain
https://www.readbyqxmd.com/read/29184507/kir2-1-nav1-5-channel-complexes-are-differently-regulated-than-kir2-1-and-nav1-5-channels-alone
#9
Raquel G Utrilla, Paloma Nieto-Marín, Silvia Alfayate, David Tinaquero, Marcos Matamoros, Marta Pérez-Hernández, Sandra Sacristán, Lorena Ondo, Raquel de Andrés, F Javier Díez-Guerra, Juan Tamargo, Eva Delpón, Ricardo Caballero
Cardiac Kir2.1 and Nav1.5 channels generate the inward rectifier K+ (IK1) and the Na+ (INa) currents, respectively. There is a mutual interplay between the ventricular INa and IK1 densities, because Nav1.5 and Kir2.1 channels exhibit positive reciprocal modulation. Here we compared some of the biological properties of Nav1.5 and Kir2.1 channels when they are expressed together or separately to get further insights regarding their putative interaction. First we demonstrated by proximity ligation assays (PLAs) that in the membrane of ventricular myocytes Nav1...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29161016/selective-voltage-gated-sodium-channel-peptide-toxins-from-animal-venom-pharmacological-probes-and-analgesic-drug-development
#10
Ying Wu, Hui Ma, Fan Zhang, Chun-Lei Zhang, Xiaohan Zou, Zhengyu Cao
Voltage-gated sodium channels (Navs) play critical roles in action potential generation and propagation. Nav channelopathy as well as pathological sensitization contribute to allodynia and hyperalgesia. Recent evidence has demonstrated the significant roles of Nav subtypes (Nav1.3, 1.7, 1.8 and 1.9) in nociceptive transduction and therefore these Navs may represent attractive targets for analgesic drug discovery. Animal toxins are structurally diverse peptides that are highly potent yet selective on ion channel subtypes and therefore representing valuable probes to elucidate the structures, gating properties and cellular functions of ion channels...
November 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29142310/sodium-channel-nav1-3-is-important-for-enterochromaffin-cell-excitability-and-serotonin-release
#11
Peter R Strege, Kaitlyn Knutson, Samuel J Eggers, Joyce H Li, Fan Wang, David Linden, Joseph H Szurszewski, Lorin Milescu, Andrew B Leiter, Gianrico Farrugia, Arthur Beyder
In the gastrointestinal (GI) epithelium, enterochromaffin (EC) cells are enteroendocrine cells responsible for producing >90% of the body's serotonin (5-hydroxytryptamine, 5-HT). However, the molecular mechanisms of EC cell function are poorly understood. Here, we found that EC cells in mouse primary cultures fired spontaneous bursts of action potentials. We examined the repertoire of voltage-gated sodium channels (NaV) in fluorescence-sorted mouse EC cells and found that Scn3a was highly expressed. Scn3a-encoded NaV1...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29122010/expression-of-voltage-gated-sodium-channel-nav1-5-in-non-metastatic-colon-cancer-and-its-associations-with-estrogen-receptor-er-%C3%AE-expression-and-clinical-outcomes
#12
Jianhong Peng, Qingjian Ou, Xiaojun Wu, Rongxin Zhang, Qian Zhao, Wu Jiang, Zhenhai Lu, Desen Wan, Zhizhong Pan, Yujing Fang
BACKGROUND: Voltage-gated sodium channel 1.5 (Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. The present study aimed to explore the associations of Nav1.5 expression with clinical outcomes and estrogen receptor-β (ER-β) expression in non-metastatic colon cancer patients receiving radical resection. METHODS: A total of 269 consecutive patients with pathologically confirmed stages I-III colon cancer who underwent radical resection were selected...
November 9, 2017: Chinese Journal of Cancer
https://www.readbyqxmd.com/read/29106681/common-missense-variant-of-scn9a-gene-is-associated-with-pain-intensity-in-patients-with-chronic-pain-from-disc-herniation
#13
Mateusz Kurzawski, Marcin Rut, Violetta Dziedziejko, Krzysztof Safranow, Anna Machoy-Mokrzynska, Marek Drozdzik, Monika Bialecka
Objective: Lumbar intervertebral disk herniation (LDH) is considered one of the major risk factors for lower back pain, mainly caused by irritation of a spinal nerve or its root. One of the genes related to pain perception is SCN9A, which encodes the voltage gated sodium channel NaV1.7, a key molecule involved in peripheral pain processing. It had been presented before that a common polymorphism within SCN9A (rs6746030: G > A, R1150W) might influence nociception in the general population...
November 2, 2017: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
https://www.readbyqxmd.com/read/29101013/the-congenital-long-qt-syndrome-type-3-an-update
#14
REVIEW
Andrés Ricardo Pérez-Riera, Raimundo Barbosa-Barros, Rodrigo Daminello Raimundo, Marianne Penachini da Costa de Rezende Barbosa, Isabel Cristina Esposito Sorpreso, Luiz Carlos de Abreu
Congenital long QT syndrome type 3 (LQT3) is the third in frequency compared to the 15 forms known currently of congenital long QT syndrome (LQTS). Cardiac events are less frequent in LQT3 when compared with LQT1 and LQT2, but more likely to be lethal; the likelihood of dying during a cardiac event is 20% in families with an LQT3 mutation and 4% with either an LQT1 or an LQT2 mutation. LQT3 is consequence of mutation of gene SCN5A which codes for the Nav1.5 Na+ channel α-subunit and electrocardiographically characterized by a tendency to bradycardia related to age, prolonged QT/QTc interval (mean QTc value 478 ± 52 ms), accentuated QT dispersion consequence of prolonged ST segment, late onset of T wave and frequent prominent U wave because of longer repolarization of the M cell across left ventricular wall...
October 31, 2017: Indian Pacing and Electrophysiology Journal
https://www.readbyqxmd.com/read/29097069/dose-related-ethanol-intake-cx43-and-nav1-5-remodeling-exploring-insights-of-altered-ventricular-conduction-and-qrs-fragmentation-in-excessive-alcohol-users
#15
Chung-Lieh Hung, Yu-Jun Lai, Po-Ching Chi, Liang-Chia Chen, Ya-Ming Tseng, Jen-Yuan Kuo, Cheng-I Lin, Yao-Chang Chen, Shing-Jong Lin, Hung-I Yeh
BACKGROUND: Chronic, excessive ethanol intake has been linked with various electrical instabilities, conduction disturbances, and even sudden cardiac death, but the underlying cause for the latter is insufficiently delineated. METHODS: We studied surface electrocardiography (ECG) in a community-dwelling cohort with moderate-to-heavy daily alcohol intake (grouped as >90g/day, ≤90g/day, and nonintake). RESULTS: Compared with nonintake, heavier alcohol users showed markedly widened QRS duration and higher prevalence of QRS fragmentation (64...
October 31, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29063143/the-nav1-7-blocker-protoxin-ii-reduces-burn-injury-induced-spinal-nociceptive-processing
#16
Jose Vicente Torres-Pérez, Pavel Adamek, Jiri Palecek, Marcela Vizcaychipi, Istvan Nagy, Angelika Varga
Controlling pain in burn-injured patients poses a major clinical challenge. Recent findings suggest that reducing the activity of the voltage-gated sodium channel Nav1.7 in primary sensory neurons could provide improved pain control in burn-injured patients. Here, we report that partial thickness scalding-type burn injury on the rat paw upregulates Nav1.7 expression in primary sensory neurons 3 h following injury. The injury also induces upregulation in phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB), a marker for nociceptive activation in primary sensory neurons...
October 23, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/29017927/eleclazine-exhibits-enhanced-selectivity-for-long-qt-syndrome-type-3-associated-late-na-current
#17
Nesrine El-Bizri, Cheng Xie, Lynda Liu, James Limberis, Michael Krause, Ryoko Hirakawa, Steven Nguyen, Dennis R Tabuena, Luiz Belardinelli, Kristopher M Kahlig
BACKGROUND: Eleclazine (GS-6615) is a sodium channel blocker designed to improve the selectivity for cardiac late Na+ current (INa) over peak INa. OBJECTIVES: The goals of this study were to investigate the inhibition of late INa by eleclazine using a sample of long QT syndrome type 3 (LQT3) and overlap LQT3/Brugada syndrome mutant channels; to compare the apparent binding rates for eleclazine with those for other class 1 antiarrhythmic agents; and to investigate the binding site...
October 7, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28990532/a-novel-scn9a-mutation-f826y-in-primary-erythromelalgia-alters-the-excitability-of-nav1-7
#18
B Wu, Y Zhang, H Tang, Mei Yang, Hai Long, Gaoxing Shi, Jianguang Tang, Xiaoliu Shi
Primary erythromelalgia (PE) is a dominant inherited disorder characterized by recurrent pain, redness, and warmth of the extremities that is caused by gain-of-function mutations in the voltage-gated sodium channel Nav1.7. We investigated a three-generation Chinese Han family with PE. The proband is a 15-year old girl presented with skin ulcers, recurrent burning pain, warmth, and redness of the lower extremities that are refractory to all kinds of reported medications. The other two patients presented with similar symptoms but with far less severity that naturally remitted near their forties...
October 9, 2017: Current Molecular Medicine
https://www.readbyqxmd.com/read/28939386/investigation-into-the-role-of-an-extracellular-loop-in-mediating-proton-evoked-inhibition-of-voltage-gated-sodium-channels
#19
Elisa Harms, Carsten Stoetzer, Thomas Stueber, Andrias O O'Reilly, Andreas Leffler
Proton-evoked activation of sensory neurons is counteracted by inhibition of voltage-gated Na(+) channels, and the low acid-sensitivity of sensory neuron of the African naked mole-rat (ANMr) was reported to be due to a strong proton-evoked block of ANMrNav1.7. Here we aimed to reevaluate the role of the suggested negatively-charged motif in the ANMrNav1.7 domain IV P-loop for inhibition by protons. Patch clamp recordings were performed on the recombinant α-subunits Nav1.2-1.8. The insertion of the negatively charged motif (EKE) of ANMrNav1...
November 20, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28905186/antidepressants-inhibit-nav1-3-nav1-7-and-nav1-8-neuronal-voltage-gated-sodium-channels-more-potently-than-nav1-2-and-nav1-6-channels-expressed-in-xenopus-oocytes
#20
Takafumi Horishita, Nobuyuki Yanagihara, Susumu Ueno, Dan Okura, Reiko Horishita, Tomoko Minami, Yuichi Ogata, Yuka Sudo, Yasuhito Uezono, Takeyoshi Sata, Takashi Kawasaki
Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Nav) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Nav1...
December 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
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