Effects on sodium channels

It has been suggested that phenol exposure results in cardiac effects because it blocks the cardiac sodium channel subtype, with little effect on sodium channels in skeletal muscle (Zamponi et al. 1994). Phenol does not appear to be carcinogenic following oral exposure (NCI 1980), although the chemical combinations that result from benzene and phenol metabolism may contain compounds that do initiate or promote cancer. Metabolites such as hydroquinone and catechol have been demonstrated to be genotoxic and clastogenic. 

Dofetilide s mechanism of action involves blockade of the cardiac ion channel that carries the rapid component of the delayed rectifier potassium current, IKr. Dofetilide inhibits IKr with no significant effects on other repolarizing potassium currents (e.g., IKs, IKl) over a wide range of concentrations. At plasma concentrations within the therapeutic range, dofetilide has no effect on sodium channels or on either i- or p-adreno-ceptors. 

Mechanism of Action A selective potassium channel blocker that prolongs repolar-ization without affecting conduction velocity by blocking one or more time-dependent potassium currents. Dofetilide has no effect on sodium channels or adrenergic alpha or beta receptors. Therapeutic Effect Terminates reentrant tachyarrhythmias,... 

Further studies have revealed that pumiliotoxin B interacts with voltage-dependent sodium channels to elicit an increased influx of sodium ions (101,102) and, in brain and heart preparations, a stimulation of phosphoino-sitide breakdown (101,103-106). The phosphoinositide breakdown can, via inositol trisphosphate, cause release of calcium from internal storage sites. The cardiotonic activity of pumiliotoxin B and various congeners and synthetic analogs correlates well with the stimulation of phosphoinositide breakdown (104,105). A number of studies on stimulation of sodium uptake by pumiliotoxin B and inhibition by local anesthetics and other agents have appeared (106-108). The effects of pumiliotoxin B on neuromuscular preparations have been reinterpreted as due primarily to effects on sodium channels, although additional direct effects on calcium mobilization remain possible (109). It has recently been proposed that pumiliotoxin B enhances the rate of activation of sodium channels (110). One characteristic effect of pumiliotoxin B is to elicit repetitive firing in neurons, apparently because of effects on sodium channel function (109-111). 

In this paper, we report that DDT and its analogs, as well as pyrethroids, enhance veratridine-dependent sodium uptake in mouse brain synaptosomes. We also demonstrate the extension of these methods to study insecticide effects on sodium channel function in rainbow trout. 

Table II. Effects on Sodium Channel Activation and Acute Intracerebral Toxicity of Deltamethrin, NRDC 157, and Their Enantiomers in Mice3...

Grammon DW, Sanders G. Pyrethroid-receptor interactions stereospecific binding and effects on sodium channels in mouse brain preparations. Neurotoxicology 1985 6 35-46. 

A. Feibamate has effects on sodium channels, enhances activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and blocks W-methyl-D-aspartate (NMDA) receptors. 

A number of substances increase the sodium permeability of excitable membranes. Their effects on sodium channels are unclear. For example, when a substance causes a permeability increase which is blocked by TTX, then it may be acting directly on the channel or indirectly on some binding site or receptor adjacent to, or some distance from, the channel. It is not easy to distinguish these possibilities in many instances. 

Standker, L., Beress, L., Garateix, A., Christ, T, Ravens, U., Salceda, E., Soto, E., John, H, Eorssmann, W.-G., and Aneiros, A. (2006) A new toxin from the sea anemone Condylactis gigantea with effect on sodium channel inactivation. Toxicon, 48, 211-220. 

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