Differences in steady-state inactivation between Na channel isoforms affect local anesthetic binding affinity

Abstract

Cocaine and lidocaine are local anesthetics (LAs) that block Na currents in excitable tissues. Cocaine is also a cardiotoxic agent and can induce cardiac arrhythmia and ventricular fibrillation. Lidocaine is commonly used as a postinfarction antiarrhythmic agent. These LAs exert clinically relevant effects at concentrations that do not obviously affect the normal function of either nerve or skeletal muscle. We compared the cocaine and lidocaine affinities of human cardiac (hH1) and rat skeletal (mu 1) muscle Na channels that were transiently expressed in HEK 293t cells. The affinities of resting mu 1 and hH1 channels were similar for cocaine (269 and 235 microM, respectively) and for lidocaine (491 and 440 microM, respectively). In addition, the affinities of inactivated mu 1 and hH1 channels were also similar for cocaine (12 and 10 microM, respectively) and for lidocaine (19 and 12 microM, respectively). In contrast to previous studies, our results indicate that the greater sensitivity of cardiac tissue to cocaine or lidocaine is not due to a higher affinity of the LA receptor in cardiac Na channels, but that at physiological resting potentials (-100 to -90 mV), a greater percentage of hH1 channels than mu 1 channels are in the inactivated (i.e., high-affinity) state.

Structural Basis of Differences in Isoform-Specific Gating and Lidocaine Block between Cardiac and Skeletal Muscle Sodium Channels

“…In particular, cardiac Na ϩ channels activate at a greater number of negative membrane potentials and are more sensitive to local anesthetics than are their skeletal muscle and nerve counterparts (Nuss et al, 1995;Wang et al, 1996;Wright et al, 1997). Clinically, 5 to 20 M lidocaine alters cardiac conduction by blocking Na ϩ channels, whereas Ͼ100 M is required to produce local anesthesia in nerve and skeletal muscle (Gianelly et al, 1967;Jewitt et al, 1968;Hille, 1978).…”

“…Clinically, 5 to 20 M lidocaine alters cardiac conduction by blocking Na ϩ channels, whereas Ͼ100 M is required to produce local anesthesia in nerve and skeletal muscle (Gianelly et al, 1967;Jewitt et al, 1968;Hille, 1978). Despite advances in our understanding of the general mechanisms of LA block of Na ϩ channels, it remains controversial whether the enhanced drug sensitivity of the cardiac channels results from gating differences (Wright et al, 1997) or from an intrinsic difference in drug affinity (Nuss et al, 1995;Wang et al, 1996). In any case, the structural basis of isoform-specific differences in gating and drug sensitivity is poorly defined.…”

“…Local anesthetics (LAs) are known to exert their clinical effects by binding preferentially to inactivated Na ϩ channels, which is the channel conformation that accumulates during rapid repetitive activity (Courtney, 1975;Hille, 1977;Hondeghem and Katzung, 1977). The enhanced drug sensitivity of the cardiac channels may simply reflect the fact that the inactivated conformation predominates under physiological conditions (Wright et al, 1997). Alternatively, cardiac channels may bind LAs with an intrinsically higher affinity (Nuss et al, 1995;Wang et al, 1996).…”

Cardiac-Specific External Paths for Lidocaine, Defined by Isoform-Specific Residues, Accelerate Recovery From Use-Dependent Block

“…22,23 Consequently, we compared lidocaine-induced UDB in the background of the cardiac isoform between the wild-type that has known QX access and mutants containing a single residue substitution in the D4 P-loop and D4S6 that should reduce access. In addition, we studied the reverse mutations in the skeletal muscle isoform for comparison with prior QX studies.…”

Interaction of phenol derivatives with ion channels

“…The increase in the fraction of inactivated with respect to resting channels on membrane depolarization, the so-called steady-state voltagedependence of inactivation, differs strongly between sodium channel isoforms from different tissues and between normal and mutant sodium channels. It has previously been shown that differences in the voltage-dependence of channel inactivation account for differences in sensitivity to sodium channel blocking agents with different binding affinities to resting with respect to inactivated channels between mutant and normal channels [18,50] and between sodium channel isoforms from different tissues [51,52]. Thus, mutant as well as sodium channels damaged by hypoxia, may increase sensitivity to a blocking drug by changing the voltage-dependence of channel inactivation [18,53].…”