Cardiac sodium channels (hH1) are intrinsically more sensitive to block by lidocaine than are skeletal muscle (μ1) channels

When lidocaine is given systemically, cardiac Na channels are blocked preferentially over those in skeletal muscle and nerve. This apparent increased affinity is commonly assumed to arise solely from the fact that cardiac Na channels spend a large fraction of their time in the inactivated state, which exhibits a high affinity for local anesthetics. The oocyte expression system was used to compare systematically the sensitivities of skeletal (μ1-β₁) and cardiac (hH1-β₁) Na channels to block by lidocaine, under conditions in which the only difference was the choice of α subunit. To check for differences in tonic block, Na currents were elicited after 3 min of exposure to various lidocaine concentrations at -100 mV, a potential at which both hH1-β₁ and μ1-β₁ channels were fully reprimed. Surprisingly, hH1-β₁ Na channels were threefold more sensitive to rested- state block by lidocaine (402 ± 36 μM, n = 4-22) than were μ1-β₁ Na channels (1,168 ± 34 μM, n = 7-19). In contrast, the inactivated state binding affinities determined at partially depolarized holding potentials (h(∞)≃0.2) were similar (K(d) = 16 ± 1 μM, n = 3-9 for hH1-β₁ and 12 ± 2 μM, n = 4-11 μ1-β₁). Lidocaine produced more use-dependent block of peak hH1-β₁ Na current elicited by trains of short(10 ms) or long- (1 s) duration step depolarizations (0.5 Hz, -20 mV) than of μ1-β₁ Na current. During exposure to lidocaine, hH1-β₁ channels recover from inactivation at -100 mV after a prolonged delay (20 ms), while μ1-β₁ channels begin reprinting immediately. The overall time course of recovery from inactivation in the presence of lidocaine is much slower in hH1-β₁ than in μ1-β₁ channels. These unexpected findings suggest that structural differences in the α subunits impart intrinsically different lidocaine sensitivities to the two isoforms. The differences in steady state affinities and in repriming kinetics are both in the correct direction to help explain the increased potency of cardiac Na channel block by local anesthetics.