Key result
Cocaine and lidocaine show similar Na channel affinities, linking greater cardiac sensitivity to resting inactivated channels.
The greater sensitivity of cardiac tissue to cocaine and lidocaine is driven by a higher proportion of cardiac Na channels being in the high-affinity inactivated state at physiological resting potentials, rather than a difference in intrinsic receptor affinity.
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Explains cardiac Na channel sensitivity via inactivation state rather than affinity; hypothesis-generating for state-dependent blocker design.
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.
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Wright et al. (1997) studied this question. Cocaine and lidocaine vs. Human cardiac (hH1) vs rat skeletal (mu 1) muscle Na channels was evaluated on Affinities of resting and inactivated mu 1 and hH1 channels for cocaine and lidocaine. Cocaine and lidocaine affinities were similar for human cardiac and rat skeletal muscle Na channels, indicating greater cardiac sensitivity is due to more inactivated channels at resting potentials.
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