临床皮肤病学研究杂志

Polidocanol Inhibits Voltage-Gated Sodium Currents

Steven Evans M1*, Benton Maglinger G2, Matthew Gayhart G3, Krishnakanth Madireddy N1 and Stephen Johnson R4

Background: Polidocanol is used as a sclerosing agent for varicose and spider veins. Its presumed mechanism of action is endothelial cytotoxicity, but it was originally developed as an anesthetic, and also has antipruritic and antitussive effects. The mechanism of action of local anesthetics is inhibition of voltagegated sodium (Na+) channels. We asked whether polidocanol, like local anesthetics, inhibits voltage-gated sodium currents. Methods: We used whole cell voltage clamp recording to test polidocanol effects on Na+ currents, and trypan blue exclusion to assess cytotoxicity in catecholamine A differentiated (CAD) and N1E-115 cell lines. Results: Polidocanol at concentrations of 1 to 10 micromolar strongly inhibited voltage-gated Na+ currents, a potency similar to that of local anesthetics. Na+ current inhibition was concentrationdependent, with an IC50 of 1.59 micromolar and 90% inhibition at 10 micromolar. Both tonic (non-use-dependent) and phasic (usedependent) inhibition occurred. Another polyethylene glycol (PEG)- containing compound, benzonatate, was previously shown to strongly inhibit Na+ currents, but other PEG-containing compounds tested in this study, nonaethylene glycol monomethyl ether and PEG 400, had no effects. Polidocanol was cytotoxic to CAD cells, producing dose-dependent cell death with an LD50 of 159 micromolar and complete cell death at 1000 micromolar. Conclusions: We confirmed the cytoxicity of polidocanol in high concentrations, which may account for its usefulness as a vein sclerotic. We found that in much lower concentrations, similar to that of clinically-used local anesthetics, polidocanol inhibits voltagegated Na+ channels. Sodium channel inhibition may account for polidocanol’s anesthetic, antipruritic, and antitussive effects. Local anesthetic-like inhibition of Na+ currents of sensory nerve fibers in veins may account for its good tolerability as a vein sclerotic. Chemical compounds studied in this article: Polidocanol (PubChem CID: 656641); PEG-400 (PubChem CID: 4867); nonaethylene glycol monomethyl ether (PubChem CID: 11339376)