Inhibition of Na+ channels by the novel blocker PD85,639

This study examined the actions of the novel Na+ channel blocker PD85,639. In whole-cell voltage-clamp recordings from Chinese hamster ovary cells transfected with a cDNA encoding the rat brain type IIA Na+ channel and from dissociated rat brain neurons, PD85,639 attenuated Na+ currents when applied either in the external bath or in the internal pipette solution. Block had a tonic component that occurred in the absence of stimulus pulses and an additional use-dependent component that developed during a train of pulses. The EC50 for tonic block was 30 microM and was not strongly dependent on the holding potential. Use-dependent block was first detectable at 1 microM and was pronounced at higher concentrations, even at stimulus frequencies as low as 1 pulse/2 min. The marked use-dependent block was due to rapid drug binding during depolarizing pulses and very slow recovery of drug-bound channels between the pulses (tau = 11 min at -85 mV). Use-dependent block was greater at more depolarized potentials, suggesting that the drug binding site was partway across the membrane electric field. The block that developed with strong depolarizations was rapidly reversed by opening channels with trains of unblocking pulses to more negative potentials. These characteristics of block by PD85,639 suggest that it is a local anesthetic drug with novel properties.