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At least 109 records · Page 6Linked to original sources
PubMed2005

Effect of sodium channel blocker, pilsicainide hydrochloride, on net inward current of atrial myocytes in thyroid hormone toxicosis rats.

To investigate effect of pilsicainide hydrochloride (pilsicainide) on electrocardiogram (ECG) signals and action potentials (APs) of atrial myocytes, levo-thyroxine (T4, 500 microg/kg body weight) was daily injected into peritoneal cavity of Sprague-Dawley rats for 14 days. T4-treatment significantly shortened RR interval, P wave, and QRS complex durations on ECG. Although pilsicainide did not affect the heart rate, P wave and corrected QT interval (QTc) was increased in T4-treated rats. AP recordings revealed that AP durations at 20%, 50%, and 90% repolarization were significantly shortened and maximal rate of rise (Max dV/dt) was significantly increased in T4-treated rat atrial cells. Pilsicainide significantly decreased AP amplitude (APA) and Max dV/dt in both control and T4-treated rat atrial cells. Concentration-inhibition study demonstrated that pilsicainide significantly inhibited net inward current of T4-treated rats at lower concentration (IC50 of 29.2 microg/mL) than that of control rats (133 microg/mL). In conclusion, pilsicainide could decrease the conduction velocity in T4-treated rat atrium by decreasing the Max dV/dt and net inward current, which could be a possible treatment of thyrotoxicosis-induced arrhythmia.

Action Potentials↗
PubMed1994

Synthesis and pharmacological evaluation of phenylacetamides as sodium-channel blockers.

The synthesis and structure-activity relationships of a series of phenylacetamides related to N-[3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenylbenzeneacetamide (1) (PD85639) acting at the voltage-dependent Na+ channel are described. All structural variations for this study were made in the phenylacetic acid portion of these molecules, and the compounds were synthesized by coupling the appropriately substituted phenylacetic acid derivative with 3-[1-(2,6-dimethyl)piperidinyl]-propanamine using standard methods of amide formation. Compounds were tested as inhibitors of [3H]batrachtoxinin binding in rat neocortical membranes and also as inhibitors of veratridine-induced Na+ influx in Chinese hamster ovary cells expressing type IIA Na+ channels. Diphenylacetic acid derivatives with halogenated aromatic rings (12-15) were very potent in both assays, while alkoxy and alkyl substitution did not affect activity (16 and 17). Selected compounds were tested as potential neuroprotective agents in two cell culture assays involving inhibition of veratridine-induced and hypoxia-induced lactate dehydrogenase release. Compound 15 was equipotent with flunarizine, a reference compound in both neuroprotection assays.

Acetamides↗
PubMed1991

A combination of inactivated sodium channel blockers causes competitive interaction on dV/dtmax of single ventricular myocytes.

STUDY OBJECTIVE: The aim was to study an interaction between class I antiarrhythmic drugs on the cardiac sodium channels. DESIGN: The single pipette, whole cell clamp method was employed to control and record membrane potential. The maximum upstroke velocity (dV/dtmax) was measured as an index of sodium channel availability during treatment of the preparations with aprindine (5 microM) in combination with mexiletine (40 microM), and lignocaine (40 microM). EXPERIMENTAL MATERIAL: Single ventricular myocytes (n = 6-8 per experiment) isolated from guinea pig hearts were used. MEASUREMENTS AND MAIN RESULTS: Trains of depolarisation to 0 mV (0.2-2.0 Hz) were applied from the resting membrane potential (-85 mV) following a long quiescent period to evaluate "tonic" and "use dependent" decrease (block) of dV/dtmax. Additional application of mexiletine or lignocaine to aprindine resulted in an increase of tonic block and a decrease of use dependent block. Because of such counteracting action, the steady state dV/dtmax during the train of depolarisation was unaffected for mexiletine, and even increased for lignocaine. Dual exponential components of dV/dtmax recovery following a 1 s conditioning depolarisation after admixture of mexiletine or lignocaine to aprindine suggest their competitive interaction on cardiac sodium channels. CONCLUSION: A combination of class I antiarrhythmic drugs having high affinity for the inactivated state of sodium channels may cause a reductive effect on dV/dtmax through competitive displacement from common receptors.

Animals↗
PubMed1985

Comparison of known sodium-channel blockers in DFP toxicity.

Research on potential therapeutic agents for organophosphate toxicity has traditionally been directed toward blocking the action of acetylcholine on its muscarinic receptors or on reactivating the inhibited catalytic enzyme. Here, we used a whole-animal lethality paradigm to study another potential antidotal mechanism: pharmacological disruption of the sodium channel conductance associated with agonist action on cholinergic receptors. Mice were injected with several drugs which have in common the ability to block sodium-channels. Drugs tested were ketamine, phenobarbital, lidocaine, morphine, prednisolone, and lithium. All mice were injected with DFP (7.6 mg/kg) plus atropine; the treatment groups were simultaneously injected with the test drug, while controls received an equal volume of physiological saline. All the test drugs, at one or more doses, revealed protection, not only in terms of prolonging symptom onset but also in terms of mortality. The reduction in mortality was quantitatively similar for each drug. Although the various drugs could have protected by many different, coincidental mechanisms, a more parsimonious explanation is that the effect could have been due to one property which all had in common; namely, sodium-channel blockade.

Animals↗
PubMed1994

Effects of the sodium channel blocker tetrodotoxin (TTX) on cellular ion homeostasis in rat brain subjected to complete ischemia.

Anoxic depolarization (AD) and failure of the cellular ion homeostasis are suggested to play a key role in ischemia-induced neuronal death. Recent studies show that the blockade of Na+ influx significantly improved the neuronal outcome. In the present study, we investigated the effects of 10 microM tetrodotoxin (TTX) on ischemia-induced disturbances of ion homeostasis in the isolated perfused rat brain. TTX inhibited the spontaneous EEG activity, delayed the ischemia-induced tissue acidification, and significantly postponed the occurrence of AD by 65%. The [Ca2+]e elevation prior to AD was attenuated from 17.8% to 6% while the increase of the [Na+]e in this period was enhanced (from 2.9% to 7.3%). These findings implied that the ischemia-induced early cellular sodium load and the corresponding shrinkage of the extracellular space was counteracted by TTX. Our results suggest that the Na+ influx via voltage-dependent channels preceding complete breakdown of ion homeostasis is one major factor leading to cell depolarization. The massive Na+ influx coinciding with AD, however, may be mainly via non-selective cation channels or/and receptor-operated channels. Persistent Na+ influx deteriorates neuronal tissue integrity by favouring Ca2+ influx and edema formation. Blockade of ischemia-induced excessive Na+ influx is, therefore, a promising pharmacological approach for stroke treatment.

Animals↗
PubMed2006

Characterization of voltage-gated sodium-channel blockers by electrical stimulation and fluorescence detection of membrane potential.

Voltage-gated ion channels regulate many physiological functions and are targets for a number of drugs. Patch-clamp electrophysiology is the standard method for measuring channel activity because it fulfils the requirements for voltage control, repetitive stimulation and high temporal resolution, but it is laborious and costly. Here we report an electro-optical technology and automated instrument, called the electrical stimulation voltage ion probe reader (E-VIPR), that measures the activity of voltage-gated ion channels using extracellular electrical field stimulation and voltage-sensitive fluorescent probes. We demonstrate that E-VIPR can sensitively detect drug potency and mechanism of block on the neuronal human type III voltage-gated sodium channel expressed in human embryonic kidney cells. Results are compared with voltage-clamp and show that E-VIPR provides sensitive and information-rich compound blocking activity. Furthermore, we screened approximately 400 drugs and observed sodium channel-blocking activity for approximately 25% of them, including the antidepressants sertraline (Zoloft) and paroxetine (Paxil).

Cells, Cultured↗
PubMed1995

"Normal" response of the QT interval and QT dispersion following intravenous injection of the sodium channel blocker disopyramide: methodological aspects.

Measurement of the QT dispersion (the maximal interlead difference) on the surface electrocardiogram has been suggested for assessing the risk for ventricular arrhythmias and for examining drug effects and their proarrhythmic potential. The acute response of QT dispersion was assessed in 10 healthy subjects receiving disopyramide, which is known to delay repolarization and to prolong global measures thereof. The QRS, JT, and QT intervals and their dispersion were assessed at spontaneous rhythm and at atrial pacing at baseline and after an intravenous injection of disopyramide 2 mg/kg over 5 minutes. The short-term (within 30 minutes) and long-term (> or = 2 weeks) variabilities of the QT interval and the QT dispersion, expressed as the coefficient of variation, were also analyzed. At spontaneous rhythm the group average QT interval was between 369 and 375 msec, and the QT dispersion was between 33 and 37 msec; both were relatively stable over time. All subjects responded homogeneously to disopyramide with a significant QT prolongation (p < 0.001), but no consistent response of the QT dispersion was observed. This discrepancy reflects the significant difference in time-dependent variability with a coefficient of variation of spontaneous, paced, and heart rate-corrected QT dispersion between 25% and 42%, 8-42 times greater than the corresponding values of 1-4% for the QT intervals. The individual response of the QT dispersion to drug challenge should therefore be interpreted with caution. Furthermore and as a consequence, QT dispersion is less sensitive for assessing drug effects on ventricular depolarization and repolarization than the QT interval.

Adult↗
PubMed1995

Sodium channel blockers partially inhibit nicotine-stimulated 86Rb+ efflux from mouse brain synaptosomes.

The possible contribution of non-nicotinic cation channels to nicotine-stimulated 86Rb+ efflux was investigated. Dendrotoxin, charybdotoxin and apamin did not affect nicotine-stimulated 86Rb+ efflux. Although 4-aminopyridine and tetraethyl-ammonium completely inhibited nicotine-stimulated 86Rb+ efflux, the concentrations required to achieve this inhibition differed markedly from those required to inhibit K(+)-stimulated 86Rb+ efflux. Cs+ reduced basal 86Rb+ efflux, but did not affect nicotine-stimulated efflux. Tetrodotoxin completely inhibited veratridine-stimulated 86Rb+ efflux (IC50 = 3.4 nM) and partially inhibited (about 42%) nicotine-stimulated efflux (IC50 = 1.3 nM). Saxitoxin also completely inhibited veratridine-stimulated efflux (IC50 = 19.5 nM) and partially inhibited (about 47%) nicotine-stimulated efflux (IC50 = 5.4 nM). Tetrodotoxin had no significant effect on the EC50 for nicotine, but decreased the efflux rate and reduced modestly the rate of desensitization measured with prolonged exposure to nicotine. Tetrodotoxin (50 nM) also inhibited maximal nicotine-stimulated 86Rb+ efflux to approximately the same extent in each of ten brain regions examined. Nicotine-stimulated 86Rb+ efflux measured in the presence or absence of 100 nM tetrodotoxin is correlated with the density of [3H]nicotine, but not [3H]saxitoxin, binding sites in 12 regions, suggesting that the density of nicotinic receptors, not the number of Na+ channels, is the rate-limiting step for nicotine-stimulated 86Rb+ efflux. Therefore, activation of Na+ channels secondary to the stimulation of nicotinic receptors seems to contribute to the nicotine-stimulated 86Rb+ efflux observed in mouse brain synaptosomes. In contrast, no evidence for K+ channel modulation of nicotine-stimulated 86Rb+ efflux from thalamic synaptosomes was obtained.

Animals↗
PubMed1993

Effect of ischaemia and reperfusion on the extra- and intracellular distribution of glutamate, glutamine, aspartate and GABA in the rat hippocampus, with a note on the effect of the sodium channel blocker BW1003C87.

The redistribution of neurotransmitter amino acids resulting from 20 min of ischaemia was studied in the rat hippocampus by quantitative, electron microscopic immunocytochemistry and by in vivo microdialysis. Changes in the distribution of glutamate, glutamine, aspartate and GABA in various cell compartments of CA1 were analysed immediately after ischaemia or after 60 min of reperfusion, by incubating ultrathin sections with antisera raised against protein glutaraldehyde conjugates of the respective amino acids and subsequently with a secondary antibody coupled to colloidal gold particles. Transverse microdialysis probes coupled with HPLC and implanted in the same animals were used to determine the extracellular concentration of amino acids in the left hippocampus and to apply a drug (BW1003C87) believed to modify the extracellular release of amino acids induced by ischaemia. Forebrain ischaemia was induced by temporary occlusion of the common carotid arteries in rats with permanently occluded vertebral arteries. The extracellular concentrations of glutamate, aspartate and GABA increased markedly during ischaemia, but returned rapidly to normal during reperfusion. BW1003C87 (250 microM, in the dialysis fluid) did not modify the increase in extracellular concentration of amino acids during ischaemia. Glutamate-like immunoreactivity was reduced in pyramidal cell somata both immediately after ischaemia and after 60 min of reperfusion. This reduction appeared to be somewhat less pronounced for cells in the left hemisphere (perfused with BW1003C87) than in the contralateral hemisphere. Ischaemia caused no consistent changes in terminals. The ratio between the intracellular levels of glutamate and glutamine was assessed by double-labelling immunocytochemistry, using two different gold particle sizes. The glutamate-glutamine ratio in glial cells was greatly increased after ischaemia, but recovered to a normal level within 1 h of reperfusion. Aspartate-like immunoreactivity was substantially reduced in pyramidal cell somata both immediately and 60 min after ischaemia, while profiles that were immunopositive for GABA in control brains showed increased GABA immunolabelling. These results suggest that postsynaptic neuronal elements as well as glial cells contribute to the extracellular overflow of excitatory amino acids during an ischaemic event: post-synaptic elements by leaking or releasing glutamate and aspartate, and glial cells by losing their ability to convert glutamate to glutamine effectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

Long-term recordings of networks of immortalized GnRH neurons reveal episodic patterns of electrical activity.

The CNS controls reproduction through pulsatile secretion of gonadotropin-releasing hormone (GnRH). Episodic increases in the firing rate of unidentified hypothalamic neurons have been associated with downstream markers of GnRH secretion. Whether this episodic electrical activity is intrinsic to GnRH neurons, intrinsic to other "pulse generator" neurons that drive GnRH neurons, or a combination of these is unknown. To determine if GnRH neurons display episodic firing patterns in isolation from other cell types, immortalized GnRH neurons (GT1-7 cells) were cultured on multiple microelectrode arrays. Long-term, multi-site recordings of GT1-7 cells revealed repeated episodes of increased firing rate with an interval of 24.8 +/- 1.3 (SE) min that were completely eliminated by tetrodotoxin, a sodium channel blocker. This pattern was comprised of active units that fired independently as well as coincidentally, suggesting the overall pattern of electrical activity in GT1-7 cells emerges as a network property. The A-type potassium-channel antagonist 4-aminopyridine (1 mM) increased both firing rate and GnRH secretion, demonstrating the presence of A-type currents in these cells and supporting the hypothesis that electrical activity is associated with GnRH release. Physiologically relevant episodic firing patterns are thus an intrinsic property of immortalized GnRH neurons and appear to be associated with secretion. The finding that overall activity is derived from the sum of multiple independent active units within a network may have important implications for the genesis of the GnRH secretory pattern that is delivered to the target organ. Specifically, these data suggest not every GnRH neuron participates in each secretory pulse and provide a possible mechanism for the variations in GnRH-pulse amplitude observed in vivo.

4-Aminopyridine↗
PubMed1986

3H-batrachotoxinin-A benzoate binding to voltage-sensitive sodium channels: inhibition by the channel blockers tetrodotoxin and saxitoxin.

The sodium channel blockers tetrodotoxin (TTX) and saxitoxin (STX) and the channel activator batrachotoxin (BTX) produce their effects by binding to separate and distinct sites on the channel protein. The fact that TTX- and STX-modified sodium channels are blocked to sodium flux has precluded drawing any direct conclusions regarding the effect of TTX/STX on BTX binding based on electrophysiological or 22Na flux measurements. Nevertheless, these sites have been presumed to be non-interacting. In this study, 3H-batrachotoxinin-A benzoate (BTX-B), a tritiated congener of BTX, has been used to provide a direct assessment of these binding interactions. Equilibrium specific binding of 3H-BTX-B to sodium channels in vesicular preparations of mouse brain in the presence of scorpion toxin was measured using a filtration assay procedure. At 25 degrees C both TTX and STX inhibit 3H-BTX-B binding in a concentration-dependent and noncompetitive manner. This inhibition is markedly temperature-dependent, being negligible at 37 degrees C and maximal at 18 degrees C, the lowest temperature investigated. Scatchard analysis of BTX-B binding isotherms at 25 degrees C in the presence and absence of 1 microM TTX revealed that inhibition is due to a 3-fold decrease in the affinity of BTX-B binding with no change in the number of binding sites (Bmax). The concentration dependence for TTX inhibition of both specific 3H-STX and 3H-BTX-B binding is identical, suggesting that inhibition of 3H-BTX-B binding is due to a direct effect of TTX/STX binding at their specific sodium channel site. The channel blockers did not alter the binding of scorpion toxin under these assay conditions, nor did BTX-B affect the binding of 3H-STX.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Electrophysiological basis of human fallopian tubal fluid formation.

A preparation for the maintenance of human Fallopian tubal epithelial cells as a polarized layer in primary culture was used to study the electrophysiological basis of tubal fluid formation in terms of the movement of Na+, K+ and Cl- ions. Transepithelial potential difference (PD) and short-circuit current (Iscc) were recorded by mounting the epithelial cells in a modified Ussing chamber. Resistance (R) was calculated from the measurements of PD and Iscc. The epithelia, although confluent, formed a 'leaky' electrical system and resistances greater than 300 omega cm-2 were rarely achieved. The sodium channel blocker, amiloride (100 mumol l-1), produced only small effects on PD and Iscc. The potassium channel blocker, tetraethylammonium chloride (TEA) (25 mmol l-1), also produced small, but significant changes in PD, Iscc and R while the chloride channel blocker, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS) (1 mmol l-1), induced a marked increase in PD and Iscc, and a fall in R, when added to the basal surface of the cells. Bathing the apical surface of the cells with chloride-free medium also produced a marked increase in PD, Iscc and R: bathing the basal surface of the cells with chloride-free medium produced a marked decrease in PD and Iscc. Extracellular ATP (10 mumol l-1), added to either the apical or the basal surface of the cells, induced a transient increase in PD and Iscc and a decrease in R. Amiloride, TEA or furosemide had no effect on the response of the cells to ATP. SITS, applied to the apical surface, significantly reduced the response of the cells to ATP. We conclude that the major driving force for human tubal fluid formation is the transepithelial secretion of chloride ions into the oviduct lumen and that exogenous ATP is a potential modulator of secretion.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed2004

D2 dopamine receptor-mediated modulation of voltage-dependent Na+ channels reduces autonomous activity in striatal cholinergic interneurons.

Striatal cholinergic interneurons are critical elements of the striatal circuitry controlling motor planning, movement, and associative learning. Intrastriatal release of dopamine and inhibition of interneuron activity is thought to be a critical link between behaviorally relevant events, such as reward, and alterations in striatal function. However, the mechanisms mediating this modulation are unclear. Using a combination of electrophysiological, molecular, and computational approaches, the studies reported here show that D2 dopamine receptor modulation of Na+ currents underlying autonomous spiking contributes to a slowing of discharge rate, such as that seen in vivo. Four lines of evidence support this conclusion. First, D2 receptor stimulation in tissue slices reduced the autonomous spiking in the presence of synaptic blockers. Second, in acutely isolated neurons, D2 receptor activation led to a reduction in Na+ currents underlying pacemaking. The modulation was mediated by a protein kinase C-dependent enhancement of channel entry into a slow-inactivated state at depolarized potentials. Third, the sodium channel blocker TTX mimicked the effects of D2 receptor agonists on pacemaking. Fourth, simulation of cholinergic interneuron pacemaking revealed that a modest increase in the entry of Na+ channels into the slow-inactivated state was sufficient to account for the slowing of pacemaker discharge. These studies establish a cellular mechanism linking dopamine and the reduction in striatal cholinergic interneuron activity seen in the initial stages of associative learning.

Acetylcholine↗
PubMed2006

The role of sodium channels in neuropathic pain.

Our knowledge of the ion channels, receptors and signalling mechanisms involved in pain pathophysiology, and which specific channels play a role in subtypes of pain such as neuropathic and inflammatory pain, has expanded considerably in recent years. It is now clear that in the neuropathic state the expression of certain channels is modified, and that these changes underlie the plasticity of responses that occur to generate inappropriate pain signals from normally trivial inputs. Pain is modulated by a subset of the voltage-gated sodium channels, including Nav1.3, Nav1.7, Nav1.8 and Nav1.9. These isoforms display unique expression patterns within specific tissues, and are either up- or down-regulated upon injury to the nervous system. Here we describe our current understanding of the roles of sodium channels in pain and nociceptive information processing, with a particular emphasis on neuropathic pain and drugs useful for the treatment of neuropathic pain that act through mechanisms involving block of sodium channels. One of the future challenges in the development of novel sodium channel blockers is to design and synthesise isoform-selective channel inhibitors. This should provide substantial benefits over existing pain treatments.

Humans↗