Objective: The affinity of lidocaine for the α-subunit of the Na channel has been reported to be greater for heart than for non-heart α- subunits, and also to be no different. Lidocaine block has a complex voltage dependence caused by a higher affinity for the inactivated state over the resting state. Inactivation kinetics, however, depend upon the α-subunit isoform and the presence of the auxiliary β1-subunit and will affect measures of block. Methods: We studied the voltage dependence of lidocaine block of Na currents by a two microelectrode voltage clamp in oocytes injected with RNA for the Na channel α-subunits of human heart (hH1a) or a rat skeletal muscle (rSkM1) alone, or coexpressed with the β1-subunit. Results: The midpoints of availability for a 25-s conditioning potential in control solutions were -65 mV for rSkM1, -50 for rSkM1+β1, -78 mV for hH1a and -76 for hH1a+β1. The K(d) of tonic lidocaine block was measured at -90, -100, -110, -120 and -130 mV in the same oocytes. The apparent K~ for both isoforms ±β1 became greater with more negative holding potentials, but tended to reach different plateaus at -130 mV (K(d) = 2128 μM for rSkM1, 1760 μM for rSkM1 + β1, 433 for hH1a, and 887 μM for hH1a+β1). Inactivated state affinities, assessed by fitting the shift in the Boltzmann midpoint of the availability relationship to the modulated receptor model, were 4 μM for rSkM1, 1 μM for rSkM1+β1, 7 μM for hH1a and 9 μM for hH1a+β1. Conclusion: The heart Na channel α-subunits expressed in oocytes have an intrinsically higher rest state affinity for lidocaine compared to rSkM1 after the voltage- and state dependence of block are considered. Coexpression with β1 modestly increased the rest affinity of lidocaine for rSkM1, but had the opposite effect for hH1a.
Makielski, J. C., Limberis, J., Fan, Z., & Kyle, J. W. (1999). Intrinsic lidocaine affinity for Na channels expressed in Xenopus oocytes depends on α (hH1 vs. rSkM1) and β1 subunits. Cardiovascular Research, 42(2), 503–509. https://doi.org/10.1016/S0008-6363(99)00024-3