Electroporation is a biophysical phenomenon whereby short, high-voltage electrical pulses transiently increase cell membrane permeability, allowing ions and molecules to cross the membrane. Key medical applications include electrochemotherapy, gene electrotransfer, and tissue ablation therapies, with accelerating clinical adoption in cardiology for the treatment of cardiac arrhythmias. Lidocaine is a widely used local anesthetic that primarily inhibits voltage-gated sodium channels, thereby preventing the transmission of nerve signals and pain sensation. In addition to its analgesic effect, lidocaine also influences membrane properties and protein function. Preclinical studies indicate that lidocaine can increase the sensitivity of cells to electroporation. We used atomistic molecular dynamics simulations to quantify lidocaine’s impact on pore formation time in lipid bilayers at a fixed transmembrane voltage, which we used as a measure of electroporation probability. Three lipid bilayer systems were examined: two simplified membrane models (POPC and POPC/POPS) and a third, compositionally realistic bilayer comprising 15 lipid species representing a membrane domain previously identified as highly prone to electroporation. For each system, conditions comprised lidocaine-free controls and neutral or charged lidocaine at concentrations of 15 or 50 mM, with four distinct starting configurations simulated for each charge state. Simulations were performed with GROMACS at a fixed transmembrane voltage of 2.4 V, with ten independent replicates per condition. Pore formation times were computed with custom Python scripts based on the MDAnalysis library. Both neutral and charged lidocaine reduced the time required for pore formation relative to controls, with the magnitude of the effect depending on membrane composition and on lidocaine’s charge state and concentration. These results confirm that lidocaine can act as an electroporation modulator, with implications for the design and optimization of protocols combining electroporation with lidocaine administration.
Šmerc et al. (Sun,) studied this question.