Cardiac-specific external paths for lidocaine, defined by isoform-specificresidues, accelerate recovery from use-dependent block

Local anesthetic antiarrhythmic drugs block voltage-gated Na+ channels from the cytoplasmic side. In addition, cardiac Na+ channels can be also blocke d by the membrane-impermeant local anesthetic QX via external paths not pre sent in skeletal muscle or brain channels. Introduction of cardiac isoform- specific residues into wild-type skeletal muscle or brain channels creates access paths for external QX block. These paths should affect the character istics of use-dependent block by influencing drug on- and off-rates. We inv estigated the effects of these external paths on drug kinetics of lidocaine , a lipophilic drug of clinical relevance, by studying use-dependent block using a two-electrode voltage clamp in Xenopus oocytes. Recovery from use-d ependent block was slowed when cardiac isoform-specific residues important for external QX access were mutated to skeletal muscle or brain isoform-spe cific residues. As the fraction of charged lidocaine was decreased by raisi ng external pH, differences in recovery kinetics diminished, indicating tha t these mutations mostly influenced block by charged lidocaine molecules. D ata were fit into a model in which bound drug distributes into charged and neutral forms based on its pK(a) and external pH with separate dissociation paths and recovery-time constants. These isoform-specific mutations altere d the recovery-time constants for the charged molecules with smaller effect s on those for the neutral molecules. We conclude that the external egress paths created by isoform-specific residues influence the drug kinetics of l idocaine, and these residues define cardiac-specific external paths for loc al anesthetic drugs.