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Patients affected by glioma frequently experience epileptic discharges; however, the causes of brain tumor-related epilepsy (BTRE) are still not completely understood. We investigated the mechanisms underlying BTRE by analyzing the effects of exosomes released by U87 glioma cells and by patient-derived glioma cells. Rat hippocampal neurons incubated for 24 hours with these exosomes exhibited increased spontaneous firing, while their resting membrane potential shifted positively by 10-15 mV. Voltage clamp recordings demonstrated that the activation of the [Na.sup.+] current shifted toward more hyperpolarized voltages by 10-15 mV. To understand the factors inducing hyperexcitability, we focused on exosomal cytokines. Western blot and ELISAs showed that TNF-[alpha] was present inside glioma-derived exosomes. Remarkably, incubation with TNF-[alpha] fully mimicked the phenotype induced by exosomes, with neurons firing continuously, while their resting membrane potential shifted positively. Real-time PCR revealed that both exosomes and TNF-[alpha] induced overexpression of the voltage-gated [Na.sup.+] channel Nav1.6, a low-threshold [Na.sup.+] channel responsible for hyperexcitability. When neurons were preincubated with infliximab, a specific TNF-[alpha] inhibitor, the hyperexcitability induced by exosomes and TNF-[alpha] was drastically reduced. We propose that infliximab, an FDA-approved drug to treat rheumatoid arthritis, could ameliorate the conditions of glioma patients with BTRE., Introduction Patients with brain tumors develop symptoms ranging from headaches to epileptic discharges to impairment of specific cognitive functions (1-3). The mechanisms leading to brain tumor-related epilepsy (BTRE) are not [...]

SCN5A encodes the voltage-gated [Na.sup.+] channel [Na.sub.v]1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure-related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. We recently generated a transcriptome-wide map of microRNA (miR) binding sites in human heart, evaluated their overlap with common SNPs, and identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within the SCN5A coding sequence. This SNP was previously shown to reproducibly associate with cardiac electrophysiological parameters, but was not considered to be causal. Here, we show that miR-24 potently suppresses SCN5A expression and that rs1805126 modulates this regulation. We found that the rs1805126 minor allele associates with decreased cardiac SCN5A expression and that heart failure subjects homozygous for the minor allele have decreased ejection fraction and increased mortality, but not increased ventricular tachyarrhythmias. In mice, we identified a potential basis for this in discovering that decreased 5cn5a expression leads to accumulation of myocardial reactive oxygen species. Together, these data reiterate the importance of considering the mechanistic significance of synonymous SNPs as they relate to miRs and disease, and highlight a surprising link between SCN5A expression and nonarrhythmic death in heart failure., Introduction The onset and clinical course of heart failure is shaped by a complex interplay of environmental and genetic factors that influence a host of biological processes, including gene regulatory [...]

Author(s): Ajit Vikram [1]; Christopher M Lewarchik [2]; Jin-Young Yoon [1]; Asma Naqvi [2]; Santosh Kumar [1]; Gina M Morgan [1]; Julia S Jacobs [1]; Qiuxia Li [1]; Young-Rae Kim [...]

Baicalin has been reported to attenuate lung edema in the process of lung injury. However, the effect of baicalin on alveolar fluid clearance (AFC) and epithelial sodium channel (ENaC) expression has not been tested. Sprague-Dawley rats were anesthetized and intratracheally injected with either 1 mg/kg lipopolysaccharide (LPS) or saline vehicle. Baicalin with various concentrations (10, 50, and 100 mg/kg) was injected intraperitoneally 30 min before administration of LPS. Then lungs were isolated for measurement of AFC, cyclic adenosine monophosphate (cAMP) level, and cellular localization of α-ENaC. Moreover, mouse alveolar type II (ATII) epithelial cell line was incubated with baicalin (30 µmol/L), adenylate cyclase inhibitor SQ22536 (10 µmol/L), or cAMP-dependent protein kinase inhibitor (PKA) KT5720 (0.3 µmol/L) 15 min before LPS (1 µg/mL) incubation. Protein expression of α-ENaC was detected by Western blot. Baicalin increased cAMP concentration and AFC in a dose-dependent manner in rats with LPS-induced acute lung injury. The increase of AFC induced by baicalin was associated with an increase in the abundance of α-ENaC protein. SQ22536 and KT5720 prevented the increase of α-ENaC expression caused by baicalin in vitro. These findings suggest that baicalin prevents LPS-induced reduction of AFC by upregulating α-ENaC protein expression, which is activated by stimulating cAMP/PKA signaling pathway. Key words: baicalin, acute lung injury, alveolar fluid clearance, epithelial sodium channel. On a rapporte que la baicaline permet d'attenuer l'redeme pulmonaire alors que le poumon subit des lesions. Cependant, l'effet de la baicaline sur la clairance du liquide alveolaire (CLA) et l'expression des canaux sodiques de la membrane apicale des cellules epitheliales (ENaC) n'apas ete teste. Nous avons injecte parvoie intratracheale des lipopolysaccharides (LPS) a 1 mg/kg ou le vehicule de solution saline a des rats Sprague-Dawley anesthesies. Trente minutes avant l'administration des LPS, nous avons injecte par voie intraperitoneale de la baicaline a diverses concentrations (10, 50 et 100 mg/kg). Puis, nous avons isole les poumons en vue de mesurer la CLA et les taux d'adenosine monophosphate cyclique (AMPc) ainsi que de localiser les canaux ENaCa dans les cellules. En outre, 15 minutes avant une incubation en presence des LPS (a 1 µg/mL), nous avons incube des lignees de cellules epitheliales alveolaires de type II (ATII) de souris en presence de baicaline (a 30 µmol/L), de SQ22536, un inhibiteur de l'adenylate cyclase, (a 10 µmol/L) ou de KT5720, un inhibiteur de la proteine kinase dependante de l'AMPc [PKA] (a 0,3 µmol/L). Enfin, nous avons determine l'expression des canaux ENaCα par immunobuvardage de western. Chez les rats presentant des lesions pulmonaires aigues provoquees par les LPS, la baicaline entrainait une augmentation proportionnelle a la dose des concentrations d'AMPc et de la CLA. L'augmentation de la CLA engendree par la baicaline etait associee a une augmentation des taux de proteines des canaux ENaC-α. Par ailleurs, le SQ22536 et le KT5720 ont empeche l'augmentation de l'expression des canaux ENaCa engendree par la baicaline in vitro. Ces resultats laissent entendre que la baicaline previendrait la diminution de la CLA provoquee par les LPS en regulant a la hausse l'expression des proteines des canaux ENaCa activee par la stimulation de la voie de signalisation AMPc/PKA. [Traduit par la Redaction] Mots-cles: baicaline, lesion pulmonaire aigue, clairance du liquide alveolaire, canaux sodiques de la membrane apicale des cellules epitheliales., Introduction Acute lung injury (ALI) is associated with high morbidity and mortality in critically ill patients. It is a distinct form of acute respiratory failure characterized by diffuse pulmonary infiltrates, [...]

Using the UM-X7.1 hereditary cardiomyopathic and muscular dystrophy hamsters (HCMH), we tested the effects of lifelong preventive or curative treatments during the heart failure phase with the NHE-1 inhibitor EMD 87580 (EMD) or with the angiotensin-converting enzyme inhibitor cilazapril on the intracellular [Na.sup.+] and [Ca.sup.2+] overloads, elevated level of NHE-1, necrosis, hypertrophy, heart failure, and early death. Our results showed that 310-day pretreatment of 30-day-old HCMHs with EMD significantly prevented cardiac necrosis, cardiomyocyte hypertrophy, and reduced the heart to body mass ratio. This treatment significantly prevented [Na.sup.+] and [Ca.sup.2+] overloads and the increase in NHE-1 protein level observed in HCMHs. Importantly, this lifelong preventive treatment significantly decreased the levels of creatine kinase and prevented early death of HCMHs. Curative 0treatment of hypertrophic 275-day-old HCMHs for 85 days with EMD significantly prevented hypertrophy and early death of HCMHs. However, treatments with cilazapril did not have any significant effects on the cardiac parameters studied or on early death of HCMHs. Our results suggest that the increase in the NHE-1 level and the consequent [Na.sup.+] and [Ca.sup.2+] overloads are implicated in the pathological process leading to heart failure and early death in HCMHs, and treatment with the NHE-1 inhibitor is promising for preventing early death in hereditary cardiomyopathy. Key words: cardiomyopathy, early death, heart failure, NHE-1, NHE-1 inhibitor EMD 87580, ACE inhibitor. A l'aide d'un modele de hamster atteint de cardiomyopathie et de dystrophie musculaire hereditaires (souche UM-X7.1), nous avons etudie les effets de traitements preventifs a vie et de traitements curatifs pendant la phase d'insuffisance cardiaque par l'administration de l'EMD 87580, un inhibiteur de la NHE-1 (isoforme 1 de la proteine echangeuse d'ions sodium-proton), ou de cilazapril, un IECA (inhibiteur de l'enzyme de conversion de l'angiotensine), sur l'etablissement de surcharges intracellulaires en [Na.sup.+] et en [Ca.sup.2+], l'augmentation des taux de NHE-1, la necrose, l'hypertrophie, l'insuffisance cardiaque et la mort prematuree. Nos resultats ont montre qu'un pretraitement des hamsters UM-X7.1 par l'EMD 87580 pendant 310 jours permettait manifestement de prevenir la necrose cardiaque, l'hypertrophie des cardiomyocytes et l'augmentation du rapport entre le poids du creur et le poids corporel total. Ce traitement permettait de prevenir l'etablissement de surcharges en [Na.sup.+] et en [Ca.sup.2+] et d'augmenter les taux de proteine NHE-1 observes dans ce modele. Mais avant tout, administre a vie de maniere preventive, ce traitement permettait de diminuer les taux de creatine kinase et de prevenir la mort prematuree de maniere importante chez les hamsters UM-X7.1. Un traitement curatif par l'EMD 87580 pendant 85 jours administre a des hamsters UM-X7.1ages de 275 jours permettait de prevenir l'hypertrophie et la mort prematuree dans ce modele. Cependant, les traitements par le cilazapril n'avaient aucun effet notable sur les parametres cardiaques etudies ni sur la mort prematuree chez les hamsters UM-X7.1. Nos resultats indiquent que l'augmentation des taux de NHE-1 et les surcharges en [Na.sup.+] et en [Ca.sup.2+] qui en decoulent joueraient un role dans les processus pathologiques entrainant l'insuffisance cardiaque et la mort prematuree chez les hamsters UM-X7.1. En fait, l'administration d'inhibiteurs de la NHE-1 pourrait etre une avenue therapeutique prometteuse pour la prevention de la mort prematuree en cas de cardiomyopathie hereditaire. [Traduit par la Redaction] Mots-cles: cardiomyopathie, mort prematuree, insuffisance cardiaque, NHE-1, inhibiteur de la NHE-1 EMD 87580, IECA., Introduction An important characteristic of several types of hypertrophy and congestive heart failure (HF) is a disturbed intracellular calcium ([[[Ca.sup.2+]].sub.i]) handling in heart muscles (Jasmin and Proschek 1984, 1994; Bkaily [...]

Background Urinary plasmin activates the epithelial [Na.sup.+] channel (ENaC) in vitro and may possibly be a mechanism of sodium retention in nephrotic syndrome (NS). This study used a paired design to test the hypothesis that remission of NS is associated with a decreased content of urinary plasmin and reduced ability of patients' urine to activate ENaC. Methods Samples were collected during active NS and at stable remission from 20 patients with idiopathic NS, aged 9.1 ± 3.2 years. Plasminogen-plasmin concentration was measured with an enzyme-linked immunosorbent assay. Western immunoblotting for plasminogen-plasmin was performed in paired urine samples. The patch clamp technique was used to test the ability of urine to evoke an inward current on collecting duct cells and human lymphocytes. Results The urinary plasminogen-plasmin/creatinine ratio was 226 [95% confidence interval (CI) 130-503] µg/mmol in nephrotic urine versus 9.5 (95% CI 8-12) µg/mmol at remission (p Conclusions These findings support the hypothesis that aberrantly filtered plasminogen-plasmin may contribute to ENaC activation and mediate primary renal sodium retention during active childhood NS. Keywords Edema * Sodium retention * Plasmin * ENaC * Aldosterone, Introduction Childhood idiopathic nephrotic syndrome (NS) is characterized by the development of severe edema, but the molecular mechanism of renal sodium retention during NS is still incompletely understood. For many [...]

Acid-sensing ion channels (ASICs) are proton-activated sodium channels of the nervous system. Mammals express four ASICs, and orthologs of these genes have been found in all chordates examined to date. Despite a high degree of sequence conservation of all ASICs across species, the response to a given increase in external proton concentration varies markedly: from large and slowly inactivating inward currents to no detectable currents. The underlying bases of this functional variability and whether it stems from differences in proton-binding sites or in structures that translate conformational changes have not been determined yet. We show here that the ASIC1 ortholog of an early vertebrate, lamprey ASIC1, does not respond to protons; however, only two amino acid substitutions for the corresponding ones in rat ASIC1, Q77L and T85L, convert lamprey ASIC1 into a highly sensitive proton-activated channel with apparent [H.sup.+] affinity of [pH.sub.50] 7.2. Addition of C73H increases the magnitude of the currents by fivefold, and W64R confers desensitization similar to that of the mammalian counterpart. Most amino acid substitutions in these four positions increase the rates of opening and closing the pore, whereas only few, namely, the ones in rat ASIC1, slow the rates. The four residues are located in a contiguous segment made by the [beta]1-[beta]2-linker, [beta]1-strand, and the external segment of the first transmembrane helix. We conclude that the segment thus defined modulates the kinetics of opening and closing the pore and that fast kinetics of desensitization rather than lack of acid sensor accounts for the absence of proton-induced currents in the parent lamprey ASIC1. epithelial sodium channel/degenerin; proton sensor; proton-sensing ion channel; channel kinetics; activation by low pH; acid-sensing ion channel doi: 10.1152/ajpcell.00100.2010.

Voltage-gated [Na.sup.+]] channel currents ([I.sub.Na]) are expressed in several types of smooth muscle cells. The purpose of this study was to evaluate the expression of [I.sub.Na], its functional role, pathophysiology in cultured human (hASMCs) and rabbit aortic smooth muscle cells (rASMCs), and its association with vascular intimal hyperplasia. In whole cell voltage clamp, [I.sub.Na] was observed at potential positive to -40 mV, was blocked by tetrodotoxin (TTX), and replacing extracellular [Na.sub.+] with N-methyl-D-glucamine in cultured hASMCs. In contrast to native aorta, cultured hASMCs strongly expressed SCN9A encoding [Na.sub.v]1.7, as determined by quantitative RT-PCR. [I.sub.Na] was abolished by the treatment with SCN9A small-interfering (si)RNA (P < 0.01). TTX and SCN9A siRNA significantly inhibited cell migration (P < 0.01, respectively) and horseradish peroxidase uptake (P < 0.01, respectively). TTX also significantly reduced the secretion of matrix metalloproteinase-2 6 and 12 h after the treatment (P < 0.01 and P < 0.05, respectively). However, neither TTX nor siRNA had any effect on cell proliferation. L-type [Ca.sup.2+] channel current was recorded, and [I.sub.Na] was not observed in freshly isolated rASMCs, whereas TTX-sensitive [I.sub.Na] was recorded in cultured rASMCs. Quantitative RT-PCR and immunostaining for [Na.sub.v]1.7 revealed the prominent expression of SCN9A in cultured rASMCs and aorta 48 h after balloon injury but not in native aorta. In conclusion, these studies show that [I.sub.Na] is expressed in cultured and diseased conditions but not in normal aorta. The [Na.sub.v]l.7 plays an important role in cell migration, endocytosis, and secretion. [Na.sub.v]1.7 is also expressed in aorta after balloon injury, suggesting a potential role for [Na.sub.v]1.7 in the progression of intimal hyperplasia. vascular smooth muscle; sodium channel; SCN9A; balloon injury

Duchenne muscular dystrophy (DMD) is a hereditary degenerative disease manifested by the absence of dystrophin, a structural, cytoskeletal protein, leading to muscle degeneration and early death through respiratory and cardiac muscle failure. Whereas the rise of cytosolic [Ca.sup.2+] concentrations in muscles of mdx mouse, an animal model of DMD, has been extensively documented, little is known about the mechanisms causing alterations in [Na.sup.+] concentrations. Here we show that the skeletal muscle isoform of the voltage-gated sodium channel, [Na.sub.v] 1.4, which represents over 90% of voltage-gated sodium channels in muscle, plays an important role in development of abnormally high [Na.sup.+] concentrations found in muscle from mdx mice. The absence of dystrophin modifies the expression level and gating properties of [Na.sub.v] 1.4, leading to an increased [Na.sup.+] concentration under the sarcolemma. Moreover, the distribution of [Na.sub.v]1.4 is altered in mdx muscle while maintaining the colocalization with one of the dystrophinassociated proteins, syntrophin [alpha]-1, thus suggesting that syntrophin is an important linker between dystrophin and [Na.sub.v]1.4. Additionally, we show that these modifications of [Na.sub.v]1.4 gating properties and increased [Na.sup.+] concentrations are strongly correlated with increased cell death in mdx fibers and that both cell death and [Na.sup.+] overload can be reversed by 3 nM tetrodotoxin, a specific [Na.sub.v] 1.4 blocker.

BACKGROUND: The growing applications of nanotechnologic products, such as quantum dots (QDs), increase the likelihood of exposure. Furthermore, their accumulation in the bioenvironment and retention in cells and tissues are [...]

The epithelial [Na.sup.+] channel (ENaC) that mediates regulated [Na.sup.+] reabsorption by epithelial cells in the kidney and lungs can be activated by endogenous proteases such as channel activating protease 1 and exogenous proteases such as trypsin and neutrophil elastase (NE). The mechanism by which exogenous proteases activate the channel is unknown. To test the hypothesis that residues on ENaC mediate protease-dependent channel activation wild-type and mutant ENaC were stably expressed in the FRT epithelial cell line using a tripromoter human ENaC construct, and protease-induced short-circuit current activation was measured in aprotinin-treated cells. The amiloride-sensitive short circuit current ([I.sub.Na]) was stimulated by aldosterone (1.5-fold) and dexamethasone (8-fold). Dexamethasone-treated cells were used for all subsequent studies. The serum protease inhibitor aprotinin decreased baseline [I.sub.Na] by approximately 50% and [I.sub.Na] could be restored to baseline control values by the exogenous addition of trypsin, NE, and porcine pancreatic elastase (PE) but not by thrombin. All protease experiments were thus performed alter exposure to aprotinin. Because NE recognition of substrates occurs with a preference for binding valines at the active site, several valines in the extracellular loops of [alpha] and [gamma] ENaC were sequentially substituted with glycines. This scan yielded two valine residues in [gamma] ENaC at positions 182 and 193 that resulted in inhibited responses to NE when simultaneously changed to other amino acids. The mutations resulted in decreased rates of activation and decreased activated steady-state current levels. There was an ~20-fold difference in activation efficiency of NE against wild-type ENaC compared to a mutant with glycine substitutions at positions 182 and 193. However, the mutants remain susceptible to activation by trypsin and the related elastase, PE. Alanine is the preferred [P.sub.1] position residue for PE and substitution of alanine 190 in the [gamma] subunit eliminated [I.sub.Na] activation by PE. Further, substitution with a novel thrombin consensus sequence (LVPRG) beginning at residue 186 in the [gamma] subunit ([[gamma].sub.Th]) allowed for [I.sub.Na], activation by thrombin, whereas wild-type ENaC was umesponsive. MALDI-TOF mass spectrometric evaluation of proteolytic digests of a 23-mer peptide encompassing the identified residues ([T.sup.I76]-[S.sup.198]) showed that hydrolysis occurred between residues V193 and M194 for NE and between A190 and S191 for PE. In vitro translation studies demonstrated thrombin cleaved the [[gamma].sub.Th] but not the wild-type [gamma] subunit. These results demonstrate that [gamma] subunit valines 182 and 193 are critical for channel activation by NE, alanine 190 is critical for channel activation by PE, and that channel activation can be achieved by inserting a novel thrombin consensus sequence. These results support the conclusion that protease binding and perhaps cleavage of the [gamma] subunit results in ENaC activation.

The voltage-gated sodium-channel type IX [alpha] subunit, known as [Na.sub.v]1.7 and encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in action potential production in these cells. Recent genetic studies have identified [Na.sub.v]1.7 dysfunction in three different human pain disorders. Gain-of-function missense mutations in [Na.sub.v]1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in [Na.sub.v]1.7 result in loss of [Na.sub.v]1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain. This review highlights these recent developments and discusses the critical role of [Na.sub.v]1.7 in pain sensation in humans., Pain is one of the most pervasive symptoms in clinical medicine; it occurs in a multitude of clinical conditions and is encountered by clinicians in every subspecialty. Yet treatment of [...]

Gain-of-function mutations or dysregulated expression of voltage-gated sodium channels can produce neuronal hyperexcitability, leading to acute or chronic pain. The sodium channel [Na.sub.v]1.7 is expressed preferentially in most slowly conducting nociceptive neurons and in sympathetic neurons. Gain-of-function mutations in the [Na.sub.v]1.7 channel lead to DRG neuron hyperexcitability associated with severe pain, whereas loss of the [Na.sub.v]1.7 channel in patients leads to indifference to pain. The contribution of [Na.sub.v]l.7 to acquired and inherited pain states and the absence of motor, cognitive and cardiac deficits in patients lacking this channel make it an attractive target for the treatment of neuropathic pain.

This study determined whether nucleotides that bind to purinergic receptors (P2R) regulate the expression or function of serum- and glucocorticoid-inducible kinase-1 (SGK1) in mouse renal inner medullar collecting duct cells (mIMCD-3). The SGK1 protein was detected by Western blotting. A significant reduction of cytosolic SGK1 expression was observed in the cells pretreated with P2R agonist adenosine 5'-O-(3-thiotriphosphate) (ATP[gamma]S), and the reduction could be reversed by P2R antagonists. This reduction was also observed in cells that were pretreated with agonists for P2R subtypes. Using ELISA, we observed a reduced SGK1 kinase activity in ATP[gamma]S-pretreated cells. This effect was reversed by P2R antagonists. Furthermore, an increase of SGK1 kinase activity in aldosterone-pretreated cells was suppressed by ATP[gamma]S. These studies demonstrate for the first time that SGK1 can be downregulated by nucleotides in renal collecting duct epithelial cells, likely via the activation of P2R, and suggest that activation of renal purinergic signaling regulates a SGK1-dependent pathway that is known to modulate ion transport in the renal collecting duct. purinergic signaling; phosphatidylinositol 4,5-bisphosphate; epithelial sodium channels; mineralocorticoid receptor; renal ion transport; serum- and glucocorticoid-inducible kinase-1

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 TFX. 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. dendritic spines | membrane potential | neurons

Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against [Na.sub.v]1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents ([IC.sub.50] = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human [Na.sub.v]1.8 ([IC.sub.50] = 8 nM) and was >100-fold selective vs. human [Na.sub.v]1.2, [Na.sub.v]1.3, [Na.sub.v]1.5, and [Na.sub.v]1.7 ([IC.sub.50] values [greater than or equal to]1 [micro]M). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation ([ED.sub.50] = 47 mg/kg, i.p.), sciatic nerve injury ([ED.sub.50] = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia ([ED.sub.50] [approximately equal to] 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection ([ED.sub.50] = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of [Na.sub.v]1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain. allodynia | electrophysiology | hyperalgesia | sensory neurons

Byline: A. S. Pivovarov (1), V. L. Nistratova (1), D. V. Boguslavskii (2) Abstract: The role of Na/Ca exchange and intracellular mobilized Ca.sup.2+ in modifying the depression of defensive behavior command neuron cholinosensitivity induced by the the Na,K pump inhibitor ouabain was studied in common snails using a cellular analog of habituation. Integral transmembrane acetylcholine-evoked currents (ACh currents) were recorded using a two-electrode membrane potential clamping technique. Decreases in neuron cholinosensitivity in the cellular analog of habituation were assessed in terms of the depth of depression of the amplitude of ACh currents during rhythmic local application of acetylcholine (with interstimulus intervals of 2--4 min) to the somatic membrane. The Na/Ca exchange inhibitor benzamyl (applied extracellularly, 15--35 uM) and two specific endoplasmic reticulum Ca-ATPase inhibitors, cyclopiazonic acid and thapsigargin (applied intracellularly, 0.1 mM) prevented modification of depression of the ACh current by ouabain (100 uM). It is concluded that Na/Ca exchange and the release of mobilized Ca.sup.2+ from intracellular calcium depots are involved in the mechanism by which the Na,K pump controls the depression of neuron cholinosensitivity in the cellular analog of habituation. Author Affiliation: (1) Department of Higher Nervous Activity, M. V. Lomonosov Moscow State University, Russia (2) Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow Article History: Registration Date: 12/10/2004

Byline: Michael Strupp (1) Author Affiliation: (1) Dept. of Neurology, Ludwig-Maximilians University, Klinikum Grosshadern, Marchioninistr. 15, 81366, Munich, Germany

Byline: Shiho Okuda (1), Fumio Kanda (1), Keisuke Nishimoto (1), Ryogen Sasaki (2), Kazuo Chihara (1) Author Affiliation: (1) Third Division, Department of Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo-ken 650-0017, Japan, Tel.: +81-78/3 82-58 85, Fax.: +81-78/3 82-58 99, E-Mail: OkudaMSA@aol.com, JP (2) Department of Neurology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie-ken 514-8507, Japan, JP Article note: Received: 28 March 2001, Received in revised form: 7 June 2001, Accepted: 11 June 2001

Individuals with Brugada syndrome and/or cardiac conduction disease are at increased risk of sudden death due to cardiac arrhythmias (irregular heartbeats). Although mutations in the SCN5A gene (which encodes NaV1.5, [...]