CARDIAC SODIUM-CHANNELS (HH1) ARE INTRINSICALLY MORE SENSITIVE TO BLOCK BY LIDOCAINE THAN ARE SKELETAL-MUSCLE (MU-1) 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 t hat cardiac Na channels spend a large fraction of their time in the in activated state, which exhibits a high affinity for local anesthetics. The oocyte expression system was used to compare systematically the s ensitivities of skeletal (mu 1-beta(1)) and cardiac (hH1-beta(1)) Na c hannels to block by lidocaine, under conditions in which the only diff erence was the choice of alpha subunit. To check for differences in to nic block, Na currents were elicited after 3 min of exposure to variou s lidocaine concentrations at -100 mV, a potential at which both hH1-b eta(1) and mu 1-beta(1) channels were fully reprimed. Surprisingly, hH 1-beta(1) Na channels were threefold more sensitive to rested-state bl ock by lidocaine (402 +/- 36 mu M, n = 4-22) than were mu 1-beta(1) Na channels (1,168 +/- 34 mu M, n = 7-19). In contrast, the inactivated state binding affinities determined at partially depolarized holding p otentials (h(x) approximate to 0.2) were similar (K-d = 16 +/- 1 mu M, n = 3-9 for hH1-beta(1) and 12 +/- 2 mu M, n = 4-11 for mu 1-beta(1)) . Lidocaine produced more use-dependent block of peak hH1-beta(1) Na c urrent elicited by trains of short- (10 ms) or long- (1 s) duration st ep depolarizations (0.5 Hz, -20 mV) than of mu 1-beta(1) Na current. D uring exposure to lidocaine, hH1-beta(1) channels recover from inactiv ation at -100 mV after a prolonged delay (20 ms), while mu 1-beta(1) c hannels begin repriming immediately. The overall time course of recove ry from inactivation in the presence of lidocaine is much slower in hH 1-beta(1) than in mu 1-beta(1) channels. These unexpected findings sug gest that structural differences in the a subunits impart intrinsicall y different lidocaine sensitivities to the two isoforms. The differenc es in steady state affinities and in repriming kinetics are both in th e correct direction to help explain the increased potency of cardiac N a channel block by local anesthetics.