State-Dependent Block of Na+ Channels by Articaine Via the Local Anesthetic Receptor

Articaine is widely used as a local anesthetic (LA) in dentistry, but little is known regarding its blocking actions on Na⁺ channels. We therefore examined the state-dependent block of articaine first in rat skeletal muscle rNav1.4 Na⁺ channels expressed in Hek293t cells. Articaine exhibited a weak block of resting rNav1.4 Na⁺ channels at −140 mV with a 50% inhibitory concentration (IC₅₀) of 378 ± 26 μM (n = 5). The affinity was higher for inactivated Na⁺ channels measured at −70 mV with an IC₅₀ value of 40.6 ± 2.7 μM (n = 5). The open-channel block by articaine was measured using inactivation-deficient rNav1.4 Na⁺ channels with an IC₅₀ value of 15.8 ± 1.5 μM (n = 5). Receptor mapping demonstrated that articaine interacted strongly with a D4S6 phenylalanine residue, which is known to form a part of the LA receptor. Thus the block of rNav1.4 Na⁺ channels by articaine is via the conserved LA receptor in a highly state-dependent manner, with a ranking order of open (23.9×) > inactivated (9.3×) > resting (1×) state. Finally, the open-channel block by articaine was likewise measured in inactivation-deficient hNav1.7 and rNav1.8 Na⁺ channels, with IC₅₀ values of 8.8 ± 0.1 and 22.0 ± 0.5 μM, respectively (n = 5), indicating that the high-affinity open-channel block by articaine is indeed preserved in neuronal Na⁺ channel isoforms.