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 (IC(50)) of 378 +/- 26 microM (n = 5). The affinity was higher for inactivated Na+ channels measured at -70 mV with an IC50 value of 40.6 +/- 2.7 microM (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 microM (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 (23.9x) > inactivated (9.3x) > resting (1x) state. Finally, the open-channel block by articaine was likewise measured in inactivation-deficient hNav1.7 and rNav1.8 Na+ channels, with IC(50) values of 8.8 +/- 0.1 and 22.0 +/- 0.5 microM, respectively (n = 5), indicating that the high-affinity open-channel block by articaine is indeed preserved in neuronal Na+ channel isoforms.