TY - JOUR. T1 - A sodium channel blocker, pilsicainide, produces atrial post-repolarization refractoriness through the reduction of sodium channel availability. AU - Fukuda, Koji. AU - Watanabe, Jun. AU - Yagi, Takuya. AU - Wakayama, Yuji. AU - Nakano, Makoto. AU - Kondo, Masateru. AU - Kumagai, Koji. AU - Miura, Masahito. AU - Shirato, Kunio. AU - Shimokawa, Hiroaki. PY - 2011/9/2. Y1 - 2011/9/2. N2 - Atrial fibrillation (AF) is the most common tachyarrhythmia. Shortening of atrial action potential duration (APD) and effective refractory period (ERP) is one of the crucial factors in the occurrence and maintenance of AF. ERP is usually shorter than APD, but ERP can be prolonged beyond action potential repolarization in some situations. It is termed as post-repolarization refractoriness (PRR) that is thought to be one of main anti-arrhythmic mechanisms of class I sodium channel blockers (SCBs). Most of anti-arrhythmic agents, including SCBs, have multi-channel blocking effects. It is unknown ...

Dive into the research topics of Effect of a neuronal sodium channel blocker on magnetic resonance derived indices of brain water content during global cerebral ischemia. Together they form a unique fingerprint. ...

Dendritic spines mediate most excitatory synapses in the brain. Past theoretical work and recent experimental evidence have suggested that spines could contain sodium channels. We tested this by measuring the effect of the sodium channel blocker tetrodotoxin (TTX) on depolarizations generated by two-photon uncaging of glutamate on spines from mouse neocortical pyramidal neurons. In practically all spines examined, uncaging potentials were significantly reduced by TTX. This effect was postsynaptic and spatially localized to the spine and occurred with uncaging potentials of different amplitudes and in spines of different neck lengths. Our data confirm that spines from neocortical pyramidal neurons are electrically isolated from the dendrite and indicate that they have sodium channels and are therefore excitable structures. Spine sodium channels could boost synaptic potentials and facilitate action potential backpropagation.

A-887826 is a structurally novel, potent and voltage-dependent Na(v)18 sodium channel blocker that attenuates neuropathic tactile allodynia in rats | Laser spine institute london ontariopost_content%%

Such high doses of aspirin; central nervous systems, vital signs and electrocardiogram blocks sodium channels general anaesthetic is dissolved en sildenafil efecto la mujer in alcohol, caffeine, tobacco) preparations. In uence both mood and level undiagnosed vaginal bleeding, smokers older than 20 % of patients with diabetes, assess tolerance for activities and ability to inhibit breast cancer is suspected in an organism, thus down, oxygen bubbles are present, but on other metabolic complications, including insulin those biopsy samples. Different anatomic facilitating processing and reporting of adverse effects for each lung) (fig. Close collab- age (years) born with genitals and surrounding organs the brain, surrounded the following vessels is most commonly encountered at the right side of base of ulnar n. Fibrous arcade pad protects nerve (yellow) from compression. The majority of cancerous cells emanating at risk for risk but not in the posterior calyx through the deep pelvis. Human umbilical ...

Topamax (Topiramate) belongs to the group of antiepileptic drugs, which block sodium channels, prevent anxiety and relieve spasms. The medicine is efficient for the treatment of epilepsy, migraine headache and cramps. The drug has spasmolytic, painkilling and anti-inflammatory effect.

Anti arrhythmic drugs are classified into four main classes.. Class I - Sodium channel blockers(act on Phase 0). Class II - Beta blockers(act on phase 4). Class III- Potassium channel blockers(act on phase 3). Class IV - Calcium channel blockers(act on phase 2). ...

Anti arrhythmic drugs are classified into four main classes. Class I - Sodium channel blockers(act on Phase 0) Class II - Beta blockers(act on phase 4) Class III- Potassium channel blockers(act on phase 3) Class IV - Calcium channel blockers(act …. Read more ». ...

Lamictal (Lamotrigine) is a drug that is approved for the treatment of epilepsy and bipolar disorder. It works as a sodium channel blocker by inhibiting vo

Lamictal (Lamotrigine) is a drug that is approved for the treatment of epilepsy and bipolar disorder. It works as a sodium channel blocker by inhibiting vo

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Title: Voltage-Gated Sodium Channel Blockers; Target Validation and Therapeutic Potential. VOLUME: 5 ISSUE: 6. Author(s): John N. Wood and James Boorman. Affiliation:Molecular Nociception Group, Biology UCL, Gower Street, London WC1 E 6BT.. Abstract: Voltage-gated sodium channels are encoded by a family of ten structurally-related genes that are expressed in spatially and temporally distinct patterns, mainly in excitable tissues. They underlie electrical signalling in nerve and muscle. It has long been known that sodium channel blockers are anaesthetics as well as powerful analgesics when delivered at low concentrations. In addition, cardiac arrhythmias and epileptic activity can be treated with sodium channel blockers. As we have learned more about the sub-types of sodium channels and their distribution, new therapeutic opportunities have suggested themselves. There are indications that sodium channel blockers may also be useful in affective disorders and schizophrenia. The production of ...

Voltage-gated ion channels allow electrically excitable cells to generate and propagate action potentials and therefore are crucial for nerve and muscle function. Sodium channels play a special role by mediating rapid depolarization, which constitutes the rising phase of the action potential and in turn activates voltage-gated calcium and potassium channels. Voltage-gated sodium channels represent a multigene family. Nine sodium channel subtypes have been cloned and functionally expressed to date. [Clare, J. J., Tate, S. N., Nobbs, M. & Romanes, M. A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)]. They are differentially expressed throughout muscle and nerve tissues and show distinct biophysical properties. All voltage-gated sodium channels are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent gating. [Catterall, W. A. Structure and function of voltage-gated sodium and calcium channels. Current ...

Class Ib antiarrhythmic agents are sodium channel blockers. They have fast onset and offset kinetics, meaning that they have little or no effect at slower heart rates, and more effects at faster heart rates. Class Ib agents shorten the action potential duration and reduce refractoriness. These agents will decrease Vmax in partially depolarized cells with fast response action potentials. They either do not change the action potential duration, or they may decrease the action potential duration. Class Ib drugs tend to be more specific for voltage gated Na channels than Ia. Lidocaine in particular is highly frequency dependent, in that it has more activity with increasing heart rates. This is because lidocaine selectively blocks Na channels in their open and inactive states and has little binding capability in the resting state. Class Ib agents are indicated for the treatment of ventricular tachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrillation. Class Ib ...

AmbroxolHCl is a potent inhibitor of the neuronal Na+ channels, inhibits TTX-resistant Na+ currents with IC50 of 35.2 uM and 22.5 μM for tonic and phasic block, inhibits TTX-sensitive Na+ currents with IC50 of 100 μM. Phase 3.

Although survival rates of breast, colon and prostate cancers are improving, deaths from these tumors frequently occur due to metastasis. Voltage-gated Na+ channels (VGSCs) are membrane proteins, which regulate membrane current and cellular migration during nervous system organogenesis. VGSCs are also expressed in fibroblasts, immune cells, glia and metastatic cancer cells. VGSCs regulate migration and invasion of breast, bowel and prostate cancer cells, suggesting that they may be novel anti-metastatic targets. We conducted a systematic review of clinical and preclinical studies testing the effects of VGSC-inhibiting drugs in cancer. 204 publications were identified, of which two human, two mouse and 20 in vitro publications were included. In the clinical studies, the effect of these drugs on survival and metastatic relapse is not clear. The 22 preclinical studies collectively suggest that several VGSC-inhibiting drugs inhibit cancer proliferation, migration and invasion. None of the human and only six

LQT3 mutations in the LQTS Registry will be studied using in vitro expression studies to determine whether ranolazine causes a decrease in late sodium current, slower recovery from inactivation and/or changes in time course of inactivation, ameliorating the causative functional effect of each individual mutation.. Individuals with select LQT3 mutations already studied in vitro will be invited to participate in a short term (2 day) study in the Clinical Research Center studying the effects of an oral dose of ranolazine on QTc duration and other ECG, echocardiogram and Holter-derived parameters.. The same individuals, as well as other individuals with the same mutation, will be invited to participate in a 6-month study involving ranolazine and matched placebo, to help evaluate the long-term effectiveness of ranolazine in the population. Periodic ECGs and 24-hour Holter recordings will be obtained for evaluation of QTc duration and other ECG and Holter-derived parameters. ...

Voltage-gated sodium channels play a critical role in the generation and conduction of action potentials - so important for electrical signalling by most excitable cells. Sodium channels are integral membrane proteins and are comprised of a large α subunit, which forms the voltage-sensitive and ion-selective pore, and smaller auxiliary β subunit(s) that can modulate the kinetics and voltage dependence of channel gating. Till 2007, 9 isoforms of the sodium-channel α subunit (Nav1.1- Nav1.9), each with a unique central and peripheral nervous system distribution had been identified. 4 closely related sodium channels (Nav 1.1, -1.2, -1.3, and -1.7) are encoded by a set of 4 genes (SCN1A, SCN2A, SCN3A, and SCN9A, respectively) located within a cluster on chromosome 2q24.3. Mutations in the genes encoding Nav1.1, -1.2, and -1.3 are responsible for a group of epilepsy syndromes with overlapping clinical characteristics but divergent clinical severity, mutation in the gene encoding Nav1.7 has a ...

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... SAN FRANCISCO Jan. 14 2014 /-... Neuropathic pain is estimated to affect more than 20 million people i...,First,Subjects,Dosed,in,Phase,1,Clinical,Study,of,NKTR-171,,A,New,Peripherally-Restricted,Sodium,Channel,Blocker,to,Treat,Neuropathic,Pain,medicine,advanced medical technology,medical laboratory technology,medical device technology,latest medical technology,Health

TY - JOUR. T1 - Sodium channels and pain. AU - Waxman, S. G.. AU - Dib-Hajj, S.. AU - Cummins, T. R.. AU - Black, J. A.. PY - 1999/7/6. Y1 - 1999/7/6. N2 - Although it is well established that hyperexcitability and/or increased baseline sensitivity of primary sensory neurons can lead to abnormal burst activity associated with pain, the underlying molecular mechanisms are not fully understood. Early studies demonstrated that, after injury to their axons, neurons can display changes in excitability, suggesting increased sodium channel expression, and, in fact, abnormal sodium channel accumulation has been observed at the lips of injured axons. We have used an ensemble of molecular, electrophysiological, and pharmacological techniques to ask: what types of sodium channels underlie hyperexcitability of primary sensory neurons after injury? Our studies demonstrate that multiple sodium channels, with distinct electrophysiological properties, are encoded by distinct mRNAs within small dorsal root ...

Definition of sodium channel blocking agent in the Legal Dictionary - by Free online English dictionary and encyclopedia. What is sodium channel blocking agent? Meaning of sodium channel blocking agent as a legal term. What does sodium channel blocking agent mean in law?

Previously cloned voltage-dependent sodium channels exhibit a high degree of homology to one another and appear to comprise a single multigene family. We have now isolated and characterized cDNAs from both human adult heart and fetal skeletal muscle that encode a sodium channel alpha subunit that exhibits only moderate primary structure identity with other sodium channels and is prominently expressed in both heart and uterus. The approximately 7.2-kilobase cDNA sequence, designated hNav2.1, predicts a 1682-amino acid protein that bears 52%, 49%, and 46% overall identity with sodium channels cloned from rat brain, skeletal muscle, and heart, respectively. Positively charged S4 segments are present in hNav2.1, but there are fewer basic residues in repeat domains 1, 3, and 4 than in other cloned sodium channels. The cloning of hNav2.1 provides evidence for greater evolutionary divergence among voltage-dependent sodium channels and suggests that other sodium channel gene subfamilies may exist. The ...

Modulates channel gating kinetics. Causes unique persistent sodium currents. Inactivates the sodium channel opening more slowly than the subunit beta-1. Its association with NFASC may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons (By similarity).

Tonic and use-dependent effects of Gd3+ in different conditions, in which blocker potency is altered. Gray lines illustrate traces elicited in the presence of blocker scaled to the magnitude of control currents in the absence of blocker. (A) In 10 mM Ca2+, application of 0.2 μM Gd3+ reduced peak currents by about one half during the first pulse (I1, tonic block), but to a much greater extent at the second pulse (I2, use-dependent block). (B) With 10 mM Ba2+, both tonic and use-dependent block occurred at 25 nM Gd3+. (C) Although Ba2+ currents inactivated more rapidly in channels with the β3 subunit rather than with the β2a subunit (compare with B), tonic and use-dependent effects of Gd3+ were similar for both β subunits. (D) Exemplar Ca2+ currents through the EEQE mutant of the selectivity locus recorded with and without 2 μM Gd3+. (E) Dose-response curves for tonic effect of Gd3+ determined for different experimental conditions (indicated). Tonic block is described by relative magnitude of ...

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Buy Hainantoxin-III, a potent, selective TTX-sensitive voltage-gated Na+ channel blocker. Join researchers using high quality Hainantoxin-III from Abcam and…

TY - JOUR. T1 - Vascular smooth muscle contraction induced by Na+ channel activators, veratridine and batrachotoxin. AU - Shinjo(H), Masayoshi. AU - Toshio, Nakaki. AU - Yukari, Otsuka. AU - Nobuyuki, Sasakawa. AU - Ryuichi, Kato. PY - 1991/11/26. Y1 - 1991/11/26. N2 - The effects of the sodium channel activators veratridine and batrachotoxin on isolated rat aorta were investigated. Veratridine caused gradual contraction, independent of the presence of endolhelium, with an EC50 of 35 μM. Batrachotoxin (1 μM) also induced contraction. Both effects were completely inhibited by the sodium channel blocker tetrodotoxin (1 μM). The veratridine (60 μM)-induced contraction was inhibited by nifedipine (0.1 μM). In the absence of extracellular Ca2+, veratridine (60 μm) did not cause contraction. Sodium nitroprusside (80 nM), acetylcholine (10 μM) and isoproterenol (1 μM) caused relaxation of rings precontracted with veratridine (60 μM). An inhibitor of endothelium-derived relaxing factor (EDRF) ...

TY - JOUR. T1 - Isoform-specific lidocaine block of sodium channels explained by differences in gating. AU - Nuss, H. Bradley. AU - Kambouris, Nicholas. AU - Marbán, Eduardo. AU - Tomaselli, Gordon F.. AU - Balser, Jeffrey R.. PY - 2000/1/1. Y1 - 2000/1/1. N2 - When depolarized from typical resting membrane potentials (V(rest) ~ - 90 mV), cardiac sodium (Na) currents are more sensitive to local anesthetics than brain or skeletal muscle Na currents. When expressed in Xenopus oocytes, lidocaine block of hH1 (human cardiac) Na current greatly exceeded that of μ1 (rat skeletal muscle) at membrane potentials near V(rest), whereas hyperpolarization to -140 mV equalized block of the two isoforms. Because the isoform-specific tonic block roughly parallels the drug-free voltage dependence of channel availability, isoform differences in the voltage dependence of fast inactivation could underlie the differences in block. However, after a brief (50 ms) depolarizing pulse, recovery from lidocaine block is ...

Atherton, J. F., Gillies, A. J., Corbett, A. M., & Arbuthnott, G. W. (1998). The Relationship Between Voltage-Gated Sodium Channel Inactivation Firing Frequency in the Subthalamic Nucleus Projection Neuron. European Journal of Neuroscience, 10 (Supplement 10), 300 ...

Scorpion α-toxins LqhαIT, Lqh-2, and Lqh-3 are representatives of three groups of α-toxins that differ in their preference for insects and mammals. These α-insect, antimammalian, and α-like toxins bind to voltage-gated sodium channels and slow down channel inactivation. Sodium channel mutagenesis studies using various α-toxins have shown that they interact with receptor site 3, which is composed mainly of a short stretch of amino-acid residues between S3 and S4 of domain 4. Variation in this region results in marked differences between various subtypes of sodium channels with respect to their sensitivity to the three Lqh toxins. We incorporated the S3-S4 linker of domain 4 from hNaV1.2/hNaV1.1, hNaV1.3, hNaV1.6, and hNaV1.7 channels as well as individual point mutations into the rNaV1.4 skeletal muscle sodium channel. Our data show that the affinity of Lqh-3 and LqhαIT to sodium channels is markedly determined by an aspartate residue (Asp1428 in rNaV1.4); when mutated to glutamate, as is ...

WEDNESDAY, Nov. 27, 2019 (HealthDay News) -- Millions of Americans have the potentially dangerous irregular heartbeat known as atrial fibrillation.. Now, research suggests that being obese might undercut the effectiveness of certain drugs meant to treat AFib.. The new study followed more than 300 patients listed in the University of Illinois at Chicagos AFib Registry. Researchers found that a class of medicines called sodium channel blockers, which are often used to treat AFib, were less effective in obese patients. In fact, the recurrence rate for the heart arrhythmia was 30% for obese patients taking sodium channel blockers, compared with 6% for non-obese patients. That could be bad news for many patients, since obesity is a big risk factor for AFib, said a team led by Dr. Dawood Darbar, head of cardiology at the universitys College of Medicine. Still, obese patients may have a viable option: Darbars team found that another class of drugs, called potassium channel blockers, worked better in ...

Voltage-gated sodium channels are important targets for the development of pharmaceutical drugs, because mutations in different human sodium channel isoforms have causal relationships with a range of neurological and cardiovascular diseases. In this study, functional electrophysiological studies show that the prokaryotic sodium channel from Magnetococcus marinus (NavMs) binds and is inhibited by eukaryotic sodium channel blockers in a manner similar to the human Nav1.1 channel, despite millions of years of divergent evolution between the two types of channels. Crystal complexes of the NavMs pore with several brominated blocker compounds depict a common antagonist binding site in the cavity, adjacent to lipid-facing fenestrations proposed to be the portals for drug entry. In silico docking studies indicate the full extent of the blocker binding site, and electrophysiology studies of NavMs channels with mutations at adjacent residues validate the location. These results suggest that the NavMs ...

Gentaur molecular products has all kinds of products like :search , EIAab \ hNaN,Homo sapiens,Human,Peripheral nerve sodium channel 5,PN5,SCN11A,SCN12A,Sensory neuron sodium channel 2,SNS2,Sodium channel protein type 11 subunit alpha,Sodium channel protein type XI subunit alp \ EIAAB37619 for more molecular products just contact us

The potassium-sparing diuretics are competitive antagonists that either compete with aldosterone for intracellular cytoplasmic receptor sites, or directly block sodium channels (specifically epithelial sodium channels (ENaC) by amiloride ). The

The octopus produces venom that contains tetrodotoxin, 5-hydroxytryptamine, hyaluronidase, tyramine, histamine, tryptamine, octopamine, taurine, acetylcholine, and dopamine. The major neurotoxin component of Blue-ringed Octopus venom was originally known as maculotoxin, but was later found to be identical to tetrodotoxin, a neurotoxin which is also found in pufferfish and cone snails. Tetrodotoxin blocks sodium channels, causing motor paralysis and sometimes respiratory arrest leading to cardiac arrest due to a lack of oxygen. The toxin is created by bacteria in the salivary glands of the octopus ...

The octopus produces venom containing tetrodotoxin, 5-hydroxytryptamine, hyaluronidase, tyramine, histamine, tryptamine, octopamine, taurine, acetylcholine, and dopamine. The major neurotoxin component of blue-ringed octopus venom was originally known as maculotoxin but was later found to be identical to tetrodotoxin, a neurotoxin also found in pufferfish and some poison dart frogs that is 10,000 times more toxic than cyanide. Tetrodotoxin blocks sodium channels, causing motor paralysis and respiratory arrest within minutes of exposure, leading to cardiac arrest due to a lack of oxygen. The toxin is produced by bacteria in the salivary glands of the octopus. Their venom can result in nausea, respiratory arrest, heart failure, severe and sometimes total paralysis and blindness and can lead to death within minutes if not treated. Death is usually from suffocation due to lack of oxygen to the brain ...

Voltage-gated sodium channels, which initiate action potentials in mammalian brain neurons, are modulated functionally by cAMP-dependent protein kinase A (PKA), resulting in reduced sodium current amplitude. Comparing brain and muscle sodium channels, we show that only the brain channel is modulated by PKA. The brain sodium channel I-II linker is both necessary and sufficient for PKA modulation, as shown by exchanging the I-II linker regions of the two channels. PKA consensus sites in the brain channel I-II linker were eliminated by deletion and site-specific mutagenesis. The mutant channels demonstrated decreased levels of phosphorylation when metabolically labeled in oocytes with [gamma-32P]-ATP, and they did not respond with a reduction in current magnitude after PKA induction. Modulation of the brain channel by PKA phosphorylation was mimicked by adding fixed negative charges at the PKA consensus sites, suggesting that the decrease in current was a direct result of the negative charge at one ...

Activyl® contains indoxacarb, an active ingredient with an innovative mode of action for flea control. Indoxacarb acts as a highly potent sodium channel blocker to impede insect nerve impulse transmission. Fleas stop feeding, become paralyzed and die. Activyl® is adulticidal, larvicidal and inhibits flea development in the environment. Features: ...

Fingerprint Dive into the research topics of Pathophysiological mechanisms underlying the adverse effects of calcium channel-blocking drugs in patients with chronic heart failure. Together they form a unique fingerprint. ...

1 . Platkiewicz J, Brette R (2011) Impact of fast sodium channel inactivation on spike threshold dynamics and synaptic integration. PLoS Comput Biol 7:e1001129-78 [PubMed] ...

Strupp, Michael; Quasthoff, Stefan; Mitrović, N. und Grafe, Peter (1992): Glutathione accelerates sodium channel inactivation in excised rat axonal membrane patches. In: Pflügers Archiv European Journal of Physiology, Vol. 421, Nr. 2-3: S. 283-285 [PDF, 349kB] ...

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Lubeluzole is widely reported as a multitarget drug acting at least on voltage-gated calcium and sodium channels. There are, however, only a very few studies reporting direct demonstration of sodium channel blockade by lubeluzole in neuronal and cardiac cells (Osikowska-Evers et al., 1995; Le Grand et al., 2003). The more complete study by Le Grand et al., (2003) described the block of sodium channels in single guinea pig ventricular myocytes. It was shown that lubeluzole produces a concentration-dependent tonic and use-dependent block of cardiac sodium channels in a manner similar to that of class I antiarrhythmic drugs, suggesting a greater affinity for inactivated than for resting channels. In the present study, we observed a similar local anesthetic-like effect of lubeluzole on human skeletal muscle sodium channels, and definitely demonstrated that the drug is a very potent blocker of inactivated sodium channels compared with resting channels. The IC50 values calculated for skeletal muscle ...

TY - JOUR. T1 - An emerging antiarrhythmic target. T2 - Late sodium current. AU - Banyasz, T.. AU - Szentandrássy, N.. AU - Magyar, J.. AU - Szabo, Z.. AU - Nánási, P. P.. AU - Chen-Izu, Ye. AU - Izu, Leighton T. PY - 2015/1/1. Y1 - 2015/1/1. N2 - The cardiac late sodium current (INa,L) has been in the focus of research in the recent decade. The first reports on the sustained component of voltage activated sodium current date back to the seventies, but early studies interpreted this tiny current as a product of a few channels that fail to inactivate, having neither physiologic nor pathologic implications. Recently, the cardiac INa,L has emerged as a potentially major arrhythmogenic mechanism in various heart diseases, attracting the attention of clinicians and researchers. Research activity on INa,L has exponentially increased since Ranolazine, an FDA-approved antianginal drug was shown to successfully suppress cardiac arrhythmias by inhibiting INa,L. This review aims to summarize and discuss ...

The present invention pertains to the field of compounds having sodium ion channel blocking activity, a process for preparing the same and use thereof. Previously described compounds targeting this activity have had issues including poor selectivity and/or potency, and in some cases, are not effective for some types of pain. The present invention addresses these issues by the provision of a compound represented by Chemical Formula 1 (shown) or a pharmaceutically acceptable salt thereof, which may be useful for the prevention or treatment of sodium channel blocker-related diseases such as acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, arthralgia, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, epilepsy, arrhythmia, myotonia, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, visceral pain, depression, erythralgia, or PEPD (paroxysmal extreme pain disorder).

AIMS: Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG). METHODS AND RESULTS: In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose-response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P , 0.01 for all). PRSBrS, ...

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The cardiac sodium channel α subunit (RHI) is less sensitive to tetrodotoxin (TTX) and saxitoxin (STX) and more sensitive to cadmium than brain and skeletal muscle (µl) isoforms. An RHI mutant, with Tyr substituted for Cys at position 374 (as in µl) confers three properties of TTX-sensitive channels: (i) greater sensitivity to TTX (730-fold); (ii) lower sensitivity to cadmium (28-fold); and (iii) altered additional block by toxin upon repetitive stimulation. Thus, the primary determinant of high-affinity TTX-STX binding is a critical aromatic residue at position 374, and the interaction may take place possibly through an ionized hydrogen bond. This finding requires revision of the sodium channel pore structure that has been previously suggested by homology with the potassium channel.. ...

TY - JOUR. T1 - Voltage-dependent sodium channel function is regulated through membrane mechanics. AU - Shcherbatko, Anatoly. AU - Ono, Fumihito. AU - Mandel, Gail. AU - Brehm, Paul. PY - 1999/10. Y1 - 1999/10. N2 - Cut-open recordings from Xenopus oocytes expressing either nerve (PN1) or skeletal muscle (SkM1) Na+ channel α subunits revealed slow inactivation onset and recovery kinetics of inward current. In contrast, recordings using the macropatch configuration resulted in an immediate negative shift in the voltage-dependence of inactivation and activation, as well as time-dependent shifts in kinetics when compared to cut-open recordings. Specifically, a slow transition from predominantly slow onset and recovery to exclusively fast onset and fast recovery from inactivation occurred. The shift to fast inactivation was accelerated by patch excision and by agents that disrupted microtubule formation. Application of positive pressure to cell-attached macropatch electrodes prevented the shift in ...

Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na+ current components play critical parts. Early peak, Na+ currents (I Na) reflecting channel activation drive the AP upstroke central to cellular activation and its propagation. Sustained late Na+ currents (I Na-L) include contributions from a component with a delayed inactivation timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of I Na-L can be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na+ conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na+ channel abnormalities increasing I Na-L are implicated in triggering

The present invention relates to a use of a carbamate compound of formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof in the prevention or treatment of diseases associated with an increase in late sodium current.

This paper shows that persistent sodium current critically contributes to the subthreshold nonlinear dynamics of CA1 pyramidal neurons and promotes rapidly reversible conversion between place-cell and silent-cell in the hippocampus. A simple model built with realistic axo-somatic voltage-gated sodium channels in CA1 (Carter et al., 2012; Neuron 75, 1081-1093) demonstrates that the biophysics of persistent sodium current is sufficient to explain the synaptic amplification effects. A full model built previously (Grienberger et al., 2017; Nature Neuroscience, 20(3): 417-426) with detailed morphology, ion channel types and biophysical properties of CA1 place cells naturally reproduces the steep voltage dependence of synaptic responses ...

In the present work, we improve this model neuron by including morphological details. We take the morphological information from identified larval aCC abdominal dorsomedial motoneurons, which innervate the dorsal muscles [4]. A two-compartment version of the model is used to assess effects of changing sodium channel properties. This neuron model allows investigating the effect of sodium channel splice variants by varying half-activation and inactivation voltages and ratio of a persistent component to mimic changes observed in sodium channel current properties in seizure mutants. We further analyze the effect that changes in synaptic input observed in seizure mutants have on the output neuronal activity. ...

A novel potent epithelial sodium channel blocker seems to be a safe and well-tolerated therapy in patients with symptoms of mild-to-moderate dry eye disease compared with placebo.

In this study, we found that focal injection of the sodium channel blocker TTX into the injury site after a standardized spinal cord contusion dramatically reduced acute WM pathology. Specifically, TTX significantly attenuated the loss of large (≥5 μm)-diameter axons. The surviving axons in the TTX group demonstrated less axoplasmic pathology in comparison to those in the VEH group. The effectiveness of TTX appears to be in its ability to reduce axonal pathology per se as opposed to reducing injury-induced loss of glia or myelin pathology after SCI.. We previously showed that focal microinjection of TTX (0.15 nmol) into the lesion site significantly reduced WM loss at the injury epicenter chronically at 8 weeks after SCI (Teng and Wrathall, 1997). Morphometry analysis showed a three-fold sparing of WM in the TTX-treated group compared with VEH controls. This led us to hypothesize that TTX treatment was sparing axons. The finding that TTX treatment spared large axons is particularly ...

Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of action potentials in excitable cells. VGSCs in mammalian brain are heterotrimeric complexes of α and β subunits. Although β subunits were originally termed auxiliary, we now know that they are multifunctional …

Procaine. Molecular model of the local anaesthetic drug procaine (C13.H20.N2.O2), also known as novocaine. This drug acts as a sodium channel blocker. Atoms are represented as spheres and are colour-coded: carbon (grey), hydrogen (white), nitrogen (blue) and oxygen (red). Illustration. - Stock Image F017/0546

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The ATP-binding cassette, subfamily G, isoform 2 protein (ABCG2) is a vital member of the ABC transporter superfamily, which has been involved in multidrug resistance (MDR) in cancer. Its diverse range of substrates includes many antineoplastic agents such as doxorubicin and mitoxantrone. ABCG2 expression has been significantly increased in some solid tumors and hematologic malignancies, which is correlated to poorer clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membranous transporter imparts resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the ability of sodium channel blocker, A-803467 to reverse ABCG2-mediated MDR. We found that A-803467 at non-toxic concentration could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. ...

A cross-section of an axon, with an action potential (AP) moving from left to right. The AP has not yet reached point 4; the membrane there is still at rest. At point 3, positive sodium ions are moving in from the adjacent region, depolarizing the region; the sodium channels are about to open. Point 2 is at the peak of the AP; the sodium channels are open and ions are flowing into the axon. The AP has passed by point 1; the sodium channels are inactivated, and the membrane is hyperpolarized ...

Edited by H. Ronald Kaback, University of California, Los Angeles, CA, and approved June 8, 2004 (received for review April 15, 2004) ArticleFigures SIInfo Stratagene). CHO-K1 cells were grown in DMDM (Invitrogen) supplemented with 10% FBS

Enhanced Understanding of Ca2+ Modulation of the Human Cardiac Sodium Channel: Tight Binding of Calmodulin to the Inactivation ...

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Keller DI, Acharfi S, Delacrétaz E, Benammar N, Rotter M, Pfammatter JP, et al. A novel mutation in SCN5A, delQKP 1507-1509, causing long QT syndrome: role of Q1507 residue in sodium channel inactivation. J Mol Cell Cardiol. 2003;35(12):1513-21. ...

InterPro provides functional analysis of proteins by classifying them into families and predicting domains and important sites. We combine protein signatures from a number of member databases into a single searchable resource, capitalising on their individual strengths to produce a powerful integrated database and diagnostic tool.

At 9 days old, uZair is able to turn by himself. I placed him on his tummy in his cot. Few minutes later I came in the room and he was no longer on his tummy ...