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

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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 (μ1) muscle Na channels that were transiently expressed in HEK 293t cells. The affinities of resting μ1 and hill channels were similar for cocaine (269 and 235 μM, respectively) and for lidocaine (491 and 440 μM, respectively). In addition, the affinities of inactivated μ1 and hill channels were also similar for cocaine (12 and 10 μM, respectively) and for lidocaine (19 and 12 μM, 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 hill channels than μ1 channels are in the inactivated (i.e., high-affinity) state.

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Wright, S. N., Wang, S. Y., Kallen, R. G., & Wang, G. K. (1997). Differences in steady-state inactivation between Na channel isoforms affect local anesthetic binding affinity. Biophysical Journal, 73(2), 779–788. https://doi.org/10.1016/S0006-3495(97)78110-4

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