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At least 19 recordsLinked to original sources
PubMed1989

Protection against nerve toxicity by monoclonal antibodies to the sodium channel blocker tetrodotoxin.

The sodium channel blocker, tetrodotoxin (TDT), was conjugated to keyhole limpet hemocyanin (KLH) and used to immunize BALB/c mice. Anti-TDT antibodies were detected in serum by ELISA and reached stable levels 4-5 wk after the first immunization. Spleens from immunized mice were fused with NS-1 mouse myeloma cells and approximately 9,329 resultant hybrids were screened by ELISA for reactivity to TDT. Two stable hybrids were isolated, subcloned, and characterized. These hybrids, termed TD13a1 and TD2C5, secreted specific anti-TDT antibodies that recognized TDT but not the related sodium channel blocker, saxitoxin (STX), as determined by competition ELISA. Both antibodies were of the IgG1k subclass with Ka's approaching 10(7) M-1. The inhibitory ability of these antibodies was tested by a competitive displacement assay for [3H]STX on rat brain membranes. Both antibodies strongly inhibited TDT binding to membranes. A nanomole of TD2C5 was able to bind approximately 1.8 nmol of TDT, whereas a comparable amount of TD13a1 bound half as much. Furthermore, TD2C5 was able to protect against TDT-induced reduction of peripheral nerve action potentials in rat tibial nerve when administered in situ. These antibodies thus represent potentially useful reagents for neurobiologic research, detection of toxin contamination and diagnosis of poisoning, and may provide protection against the toxicity of TDT in vivo.

Action Potentials↗
PubMed1996

A structure-activity relationship study of novel phenylacetamides which are sodium channel blockers.

A structure-activity relationship study of a series of novel Na(+) channel blockers, structurally related to N-[3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenylbenzeneacetamide (1, PD85639) is described. The diphenylacetic acid portion of the molecule was left unchanged throughout the study, while structural features in the amine portion and the amide alkyl linkage of the molecule were modified. The compounds were tested for inhibition of veratridine-stimulated Na(+) influx in CHO cells expressing type IIA Na(+) channels. Several derivatives show a trend toward more potent Na+ channel blockade activity with increasing lipophilicity of the amine portion of the molecule. The presence of a phenyl ring near the amine increases inhibitory potency. A three-carbon spacer between the amide and amine is optimal, and a secondary amide linkage is preferred.

Acetamides↗
PubMed1998

Postrepolarization refractoriness as a potential anti-atrial fibrillation mechanism of pilsicainide, a pure sodium channel blocker with slow recovery kinetics.

The antifibrillatory effect of pilsicainide, a sodium channel blocker with slow recovery kinetics, was investigated in a canine model of atrial fibrillation. Prolonging the atrial effective refractory period is an important mechanism for pharmacological termination of atrial fibrillation. However, the effectiveness of potassium channel blockers has been questioned because of their reverse-use-dependent property. In eight open-chest dogs, the duration of the atrial endocardial monophasic action potential and the atrial effective refractory period were determined using a Franz catheter. Conduction velocity was obtained from a 96-channel mapping electrode at multiple cycle lengths. Inducibility of sustained atrial fibrillation (> 30 minutes) was confirmed by atrial burst pacing during bilateral vagal stimulation, and local fibrillation cycle lengths were measured. Five minutes after restarting fibrillation, pilsicainide (0.6 mg/kg + 0.04 mg/kg/min) was administered. After fibrillation was terminated, measurements were repeated. Pilsicainide successfully terminated atrial fibrillation in 7 of 8 dogs after the median time of 5.1 minutes. The conduction velocity decreased significantly. Although pilsicainide did not affect monophasic action potential duration, it caused use-dependent prolongation of the atrial effective refractory period (P < 0.05), creating postrepolarization refractoriness. Accordingly, pilsicainide prolonged the atrial fibrillation cycle length from 80.6 to 113.8 ms (P < 0.05) before termination of fibrillation. Sodium channel blockers with slow recovery kinetics can prolong the atrial effective refractory period without affecting monophasic action potential duration. Unlike potassium channel blockers, these sodium channel blockers maintain postrepolarization refractoriness, even at rapid stimulation rates, thus exerting a salutary antifibrillatory effect.

Action Potentials↗
PubMed1998

Functional and structural features of gamma-zeathionins, a new class of sodium channel blockers.

Gamma1- and gamma2-zeathionins (gamma1-Z and gamma2-Z) are members of a family of small and basic peptides involved in plant protection. These plant defensins exhibit remarkable structural similarity to scorpion neurotoxins and insect defensins. In the present report, we used the whole-cell patch clamp technique to investigate the inhibition of the sodium current (I(Na)) by gamma1-Z and gamma2-Z in the GH3 cell line. Both gamma1-Z and gamma2-Z rapidly and reversibly inhibited I(Na) without changing the kinetics or voltage dependence of activation or inactivation. To our knowledge, this is the first example of a plant protein that inhibits the sodium channel. From structural comparisons with the mu-conotoxins, a family of peptides that block the sodium channel, we detected some similar features that could provide the basis of inhibition of sodium channels by gamma-zeathionins.

Amino Acid Sequence↗
PubMed1989

In vitro and in situ inhibition of the sodium channel blocker saxitoxin by monoclonal antibodies.

The sodium channel blocker saxitoxin (STX) was conjugated to keyhole limpet hemocyanin (KLH) and used to immunize BALB/c mice. Anti-STX antibodies were detected in serum by an enzyme-linked immunosorbent assay (ELISA) within a week or two after the first immunization. Spleens from immunized mice were fused with NS-1 myeloma cells and approximately 7000 resultant hybrids were screened by ELISA for reactivity to STX. Two stable hybrids were isolated, subcloned, and characterized. These hybrids, termed S1A5 and S3E.2, secreted specific anti-STX antibodies that did not recognize the closely related toxin tetrodotoxin (TDT), as determined by competition ELISA. The S1A5 monoclonal antibody (mAb) was of the IgMk class and S3E.2 of the IgG1k subclass with affinity constants (Ka values) of approximately 10(6) M-1. The protective ability of these antibodies was tested by a competitive displacement assay for [3H]STX binding on rat brain membranes. Purified S3E.2 strongly displaced [3H]STX binding, whereas S1A5 weakly inhibited [3H]STX binding to membranes. One nanomole of S3E.2 or S1A5 was able to bind 0.03 nmol or 0.005 nmol, respectively, of STX. The S3E.2 mAb offered partial protection against STX-induced reduction of peripheral nerve action potential in rat tibial nerve when administered in situ at concentrations 10- to 30-fold greater than STX. The S1A5 mAb, despite its ability to inhibit STX binding in vitro, was completely ineffectual in situ. These antibodies, particularly S3E.2, thus represent potentially useful reagents for neurobiologic research, detection of toxin contamination, and diagnosis of poisoning, and may provide protection against the toxicity of STX in vivo.

Action Potentials↗
PubMedDate not supplied

[Inhibition of Na+, K+-ATPase activity by sodium channel blockers].

Blocking agent of sodium channels in membranes of epithelial cells amiloride and triamterene as well as tetrodotoxin, which blocked sodium channels in electroexcitable membranes, were found to be effective inhibitors of Na, K-ATPase. A similarity between sodium sites of sodium channels and that of Na, K-ATPase is considered.

Amiloride↗
PubMed1997

The rise time of the monophasic action potential--a new index of local use-dependent conductivity by sodium channel blockers in human myocardium.

The kinetics of global use-dependent conduction slowing produced by sodium channel blockers in the human heart, estimated as a change in the QRS width, are known to be similar to those of use-dependent block of the maximum rate of depolarization in in vitro studies. However, the kinetics of the regional use-dependent decrease in conductivity have not been investigated. We examined whether the rise time of the monophasic action potential would be clinically useful as a marker of the local use-dependent decrease in conductivity by sodium channel blockers. In 12 patients without organic heart disease, monophasic action potentials (MAPs) were recorded at the right ventricular endocardium using a contact electrode before and after the administration of disopyramide (n = 6, 2 mg/kg, i.v.) or pilsicainide (class Ic agents, n = 4, 1 mg/kg, i.v., and n = 2, 150 mg, po) while the stimulus frequency was abruptly increased from 100/min to 150/min. The rise time, defined as the interval from the pacing pulse to the first peak deflection of the monophasic action potential, and the ORS width were measured simultaneously. In the absence of the sodium channel blockers, the abrupt increase in heart rate did not alter the QRS width or the rise time. In the presence of the agents, both variables were lengthened exponentially. The rate constants of onset changes in the QRS width and the rise time were 2.1 +/- 0.5 beats and 2.1 +/- 0.4 beats after the administration of disopyramide, and 7.5 +/- 3.0 beats and 8.2 +/- 4.0 beats after pilsicainide, respectively. The rate constant of the rise time was closely correlated with that of the QRS width. The present results are very closely comparable with the onset rate constants of use-dependent block of the maximum rate of depolarization in in vitro studies. These results suggest that (1) the rise time is a good indicator of local use-dependent decrease in conductivity by sodium channel blockers in human hearts and (2) the local use-dependent decrease in conductivity has kinetics similar to those of use-dependent sodium channel blocks.

Action Potentials↗
PubMedDate not supplied

Effects of sodium channel blockers on electrical field stimulation-induced guinea-pig tracheal smooth muscle contraction.

The effects of sodium channel blockers, a conventional one: tetrodotoxin, and clinically available ones: cibenzoline, flecainide and SUN 1165 [N-(2,6-dimethylphenyl)-8-pyrrolizidine-acetamide hydrochloride hemihydrate] on electrical field stimulation-induced and carbachol-induced guinea-pig tracheal smooth muscle contraction were investigated. Electrical field stimulation was performed at 50 V with 20 Hz and 0.8 msec square pulse duration. Carbachol (5 x 10(-8) M) was used for induction of tracheal contractions. All agents were administered before electrical field stimulation or carbachol administration. Electrical field stimulation-induced tracheal smooth muscle contraction was dose-dependently reduced by all sodium channel blockers used. The effects of sodium channel blockers on electrical field stimulation-induced contraction were greater than those on carbachol-induced contractions, except for SUN 1165 which reduced similarly both electrical field stimulation- and carbachol-induced contractions. These results indicate that the sodium influx is closely related to the acetylcholine release, resulting in smooth muscle contraction. Since the parasympathetic nervous system may be involved in the genesis of various pathological conditions, such as bronchial asthma, sodium channel blockers could contribute to the management of these conditions.

Animals↗
PubMed1991

Sodium deficient rats are unmotivated by sodium chloride solutions mixed with the sodium channel blocker amiloride.

Rats were made sodium deficient by furosemide injection and then offered 20 min of access to 0.05 M NaCl mixed with the sodium channel blocker amiloride. Compared with a sodium deficient control group that was also offered 0.05 M NaCl, these rats drank very little. A subsequent test conducted in the same manner with 20 min of access to 0.3 M NaCl mixed with amiloride produced similar results. It is concluded that amiloride blocks the neural information required for generating the attractive taste of NaCl to the sodium deficient rat.

Amiloride↗
PubMed2000

Sodium channel blockers and uridine triphosphate: effects on nasal potential difference in cystic fibrosis mice.

Sodium channel inhibitors block the enhanced Na+ reabsorption in cystic fibrosis (CF). Extracellular nucleotides facilitate Cl- secretion via Ca2+ gated Cl- channels. A combination of these effects may produce less viscid secretions in CF which are easier to expectorate. This study examined the effects of combining sodium channel blockers with uridine triphosphate (UTP) on nasal membrane potential difference (PD) in CF insertional null mutant mice (cftr(tm1HGU)), deltaF508 homozygous mice (cftr(tm1Cam)) and matched control animals. Median basal PD in the insertional CF mice and deltaF508 CF mice were -28 and -34 mV respectively. These values were significantly different to the control animals (-20 mV). Amiloride and loperamide reduced the PD in cftr(tm1HGU) CF mice (deltaPD 13 mV & 15 mV respectively) suggesting Na+ blockade. The subsequent addition of UTP in a chloride-free vehicle increased the PD (deltaPD -8- -12.5 mV). DeltaF508 mice showed significantly greater responses compared with CF insertional null mutant mice (p<0.05). The action of UTP was brief and not prolonged by the addition alpha-beta-methylene-adenosine 5' diphosphate. Suramin, a competitive antagonist of P2 purinoceptors blocked the action of UTP. In conclusion, this study demonstrated dose dependant nasal membrane potential changes in differences mice with uridine triphosphate in the presence of sodium channel blockers suggestive of chloride secretion. More stable analogues of uridine triphosphate in combination with long acting sodium channel blockers such as loperamide may have therapeutic potential in cystic fibrosis.

Amiloride↗
PubMed1991

Electrophysiological effects of sodium channel blockers on guinea pig left atrium.

The electrophysiological effects of five sodium channel blockers (mexiletine, lidocaine, disopyramide, aprindine and flecainide) on the guinea pig left atrium were investigated by recording the action potential and its maximum rate of rise (Vmax). The onset and offset kinetics of use-dependent block of Vmax were analyzed. Lidocaine, aprindine and flecainide were classified clearly as fast, intermediate and slow, respectively. Mexiletine and disopyramide had two components in onset and offset of use-dependent block. Mexiletine showed fast and intermediate kinetics, whereas disopyramide showed intermediate and slow kinetics. Action potential duration at 90% repolarization (APD) was prolonged by disopyramide and mexiletine. The other drugs did not change the action potential duration. Effective refractory period was prolonged by all drugs with relative potency in the following order: disopyramide greater than mexiletine greater than lidocaine greater than aprindine = flecainide. In conclusion, the modes of actions of sodium channel blockers on the atrium were disclosed to be different from those on the ventricle. The pharmacological therapy for atrial arrhythmias should be based on the electrophysiological effects of the drugs on the atrium, not on the ventricle.

Action Potentials↗
PubMed1999

Vanilloid receptor agonists potentiate the in vivo local anesthetic activity of percutaneously injected site 1 sodium channel blockers.

BACKGROUND: Capsaicin, the pungent ingredient in chili peppers, is a vanilloid with noxious and analgesic effects that inhibits tetrodotoxin-resistant sodium currents. Because tetrodotoxin-resistant currents are found primarily in small-diameter nociceptor afferents of the peripheral nerves, their inhibition may lead to selective analgesia. Therefore, the authors evaluated the interactions between tetrodotoxin, a site 1 sodium channel blocker, and capsaicin on nerve blockade in vivo. METHODS: Percutaneous sciatic nerve injections with 0 to 9.9 mM capsaicin, 0 to 120 microM tetrodotoxin, or both were administered to male Sprague-Dawley rats. Thermal nociceptive and motor blockade were measured. Data were expressed as medians with 25th and 75th percentiles. RESULTS: Capsaicin produced a transient increase in thermal latency with no effect on motor strength. Tetrodotoxin reduced motor strength for a longer duration than nociception. The interaction between tetrodotoxin and capsaicin was synergistic, as evidenced by (1) supraadditive prolongation of both nociceptive and motor block, with the effect of capsaicin reversed by the vanilloid antagonist capsazepine, and (2) synergism in the frequency that rats achieved maximal block shown by isobolographic analysis. The combination of tetrodotoxin and capsaicin showed less motor predominance than tetrodotoxin did alone. Similar interactions were found between tetrodotoxin and resiniferatoxin (another vanilloid), and between capsaicin and saxitoxin (another site 1 sodium channel blocker), but much less so between bupivacaine and capsaicin. CONCLUSIONS: Site 1 sodium channel blockers and vanilloids have synergistic effects on nerve blockade in vivo. These interactions may be useful in developing prolonged local anesthetics and elucidating mechanisms of functionally selective nerve blockade.

Anesthetics, Local↗
PubMed2000

Determination of refractory periods and conduction velocity during atrial fibrillation using atrial capture in dogs: direct assessment of the wavelength and its modulation by a sodium channel blocker, pilsicainide.

OBJECTIVES: The purposes of this study were to measure the atrial refractory period and the conduction velocity (CV) during atrial fibrillation (AF) and to explore the antiarrhythmic mechanism of a sodium channel blocker, pilsicainide, during AF. BACKGROUND: Sodium channel blockers not only decrease the CV, but also prolong the atrial refractory period, particularly during rapid excitation. Because these effects on the wavelength are counteractive and rate dependent, it is critical to measure these parameters during AF. METHODS: In eight dogs, after AF was induced under vagal stimulation, a single extra-stimulus was repeatedly introduced from the left atrium and its capture was statistically determined for each coupling interval. The local CV was also measured during constant capture of the fibrillating atrium by rapid pacing. The same procedure was repeated after pilsicainide administration. RESULTS: Pilsicainide significantly increased the mode of AF intervals from 81 +/- 10 to 107 +/- 16 ms (p < 0.01). While the CV was decreased from 0.9 +/- 0.1 to 0.7 +/- 0.1 m/s (p < 0.02), the effective refractory period during AF was increased from 69 +/- 11 ms to 99 +/- 17 ms (p < 0.01). As a result, the wavelength was significantly increased by pilsicainide from 6.6 +/- 0.9 to 7.6 +/- 1.2 cm (p < 0.05). CONCLUSIONS: During AF, whereas the sodium channel blocker pilsicainide decreases CV, it lengthens the wavelength by increasing the refractory period, an action that is likely to contribute to the drug's ability to terminate the arrhythmia. The direct measurement of refractoriness and CV during AF may provide new insights into the determinations of the arrhythmia and antiarrhythmic drug action.

Animals↗
PubMed1988

Cerebral cation shifts in hypoxic-ischemic brain damage are prevented by the sodium channel blocker tetrodotoxin.

We investigated the effect of the sodium channel blocker, tetrodotoxin, in two animal models of brain pathology. In the first, an acute model, we recorded the interstitial brain potential in the striatum of rats after cardiac arrest. The time of deflection of this potential, an indication of changes in cerebral cation concentrations, was determined in control rats, and in rats pretreated with intrastriatal tetrodotoxin. In control rats a deflection of the brain potential was noted 2 min after cardiac arrest; tetrodotoxin pretreatment delayed this deflection to about 5 min. The second, a survival model, was based on the Levine preparation in rats. A combination of ischemia and hypoxia produced unilateral, cerebral infarcts, which were characterized by a decrease of brain [K+], and by increases of [Ca2+] and [Na+] and thus of the Na+:K+ ratio. Data on the cation shifts, determined by chemical assay methods, were complemented by those of more conventional methods of assessment of brain damage, such as the determination of survival, of Evans blue staining, and of brain water content. Cation shifts could be prevented locally by tetrodotoxin. In conclusion, the drug can, at least partially, prevent the detrimental effects of an ischemic insult. In addition, our results showed that protective effects observed in the acute model may sometimes offer an indication of the effects to be expected in the survival model. Furthermore, the effect of tetrodotoxin on the brain potentials in the acute model showed that its protective action in the survival model may be brought about by delaying cell depolarization and by shortening the actual duration of the depolarized state. We conclude that Na+ influx and, consequently, neurotransmission may play a crucial role in the development of cerebral damage.

Animals↗
PubMed1992

Mechanisms of action of sodium channel blocker: gate-related receptor hypothesis.

A new hypothesis on mechanisms of action of the sodium channel blocker, the gate-related receptor hypothesis, has been proposed in this paper. Furthermore, a mathematic model and parameter estimation procedure for the kinetics analysis have also been given. Using the model and procedure, modeling and analyzing of cardiac sodium channel blockade by lidocaine and dauricine have been performed. The model-estimated results were not only coincident with those documented, but also provided some new information which may be helpful for understanding mechanism of blocking action of both drugs on sodium channels. The studies suggested that the gate-related receptor hypothesis is good for the elucidation of mechanisms of action of the sodium channel blocker.

Alkaloids↗
PubMed1994

Comparative study of voltage-sensitive sodium channel blockers in focal ischaemia and electric convulsions in rodents.

This study evaluates the neuroprotective properties of some voltage-sensitive sodium channel blockers in a model of focal ischaemia. After curative treatment (0.5 and 24.5 h after insult), well known voltage-sensitive sodium channel blockers, phenytoin (2 x 100 mg/kg i.p.), carbamazepine (2 x 50 mg/kg i.p.), lamotrigine (2 x 50 mg/kg i.p.) and RP 66055 (2 x 8 mg/kg i.p.) were found to protect rats against brain damage induced by occlusion of the middle cerebral artery, by 40%, 24%, 28% and 44% respectively. These compounds were also active in protecting both mice and rats against tonic convulsions induced by electroshock, Intraperitoneal ED50 values in mice and rats respectively were of 5.2 and 12.5 mg/kg for phenytoin, 8.4 and 3.6 mg/kg for carbamazepine, 4.4 and 3.1 mg/kg for lamotrigine, 3.9 and 0.22 mg/kg for RP 66055. In contrast, lifarizine was totally devoid of activity in these three tests. This study extends an accumulation of data in the literature pointing to a therapeutic potential for voltage-dependent sodium channel blockers which penetrate the blood brain barrier. Such compounds as phenytoin, carbamazepine, lamotrigine or RP 66055 may act at sodium channels to prevent depolarization, inhibit release of neurotransmitters such as glutamate and thus protects the cortex against cellular damage induced by focal ischaemia by both pre- and post-synaptic inhibition of abnormal neurotransmission.

Animals↗
PubMed1999

Effect of pilsicainide, a pure sodium channel blocker, on spiral waves during atrial fibrillation: theoretical analysis by numerical simulation.

This study investigated the effects of a particular type of sodium channel blocker, pilsicainide, on spiral waves, which are a possible mechanism of atrial fibrillation, by using numerical simulation. A meandering spiral wave was induced on a two-dimensional matrix corresponding to the isolated atrial myocardium. The model attempted to simulate the changes caused by pilsicainide. The conductivity was depressed and the refractory period was prolonged with little change in the action potential duration. The dynamic change in the refractory period depended on the preceding coupling interval. A blockline occurred and changed gradually because of the change in the refractory period. The spiral wave became a stable reentry rotating around the blockline, decreasing the excitation frequency in the matrix before rushing out of the matrix. The electrocardiogram showed a slow coarse wave, as well as a real electrocardiographic change by pilsicainide. This might, in part, explain how pilsicainide acts on atrial fibrillation. Key words: sodium channel blocker, pilsicainide, spiral wave, atrial fibrillation, computer simulation.

Anti-Arrhythmia Agents↗
PubMed1995

Electrophysiological evaluation of the sodium-channel blocker carbamazepine in healthy human subjects.

Carbamazepine (CBZ) is a sodium-channel blocker used mainly for the treatment of epileptic seizures and neuralgias. It may impair the function of the cardiac conduction system in susceptible patients, but its electrophysiological effects have not been thoroughly assessed in the normal heart, which was the aim of the present study. Ten healthy volunteers, mean age 32 years, underwent two electrophysiological investigations at baseline and three at different dose levels of CBZ. The transesophageal atrial stimulation technique was used to evaluate sinus node function, refractoriness of the atrial myocardium, atrioventricular conduction, and ventricular depolarization and repolarization (as reflected by the QRS, JT, and QT intervals) at spontaneous rhythm and after atrial pacing. Atropine was administered to facilitate 1:1 conduction and assessment of rate-dependent effects. At the highest CBZ dose (800 mg/day), which gave plasma concentrations within the upper therapeutic range, the PQ interval was mildly prolonged (151 vs. 159 msec; p < 0.01). In addition, the shortening of the JT interval normally seen at higher pacing rates was counteracted by high-dose CBZ, as demonstrated by a lower mean slope of the regression line after atropine and CBZ than after atropine alone (0.17 vs. 0.20; p < 0.05). No other effects were detected. At therapeutic levels CBZ had minimal effects on the healthy conduction system, supporting its safe use in the absence of cardiac disease.

Administration, Oral↗