Intrinsically More Sensitive to Block by Lidocaine Than Are Skeletal Muscle ( zl) 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 o f 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 o f skeletal (~1-(3a) and cardiac (hHl-[3a) Na channels to block by lidocaine, under conditions in which the only difference was the choice of 0~ subunit. To check for differences in tonic block, Na currents were elicited after 3 rain of exposure to various lidocaine concentrat ions at 1 0 0 mV, a potential at which both hHl-[3a and ~1-~31 channels were fully reprimed. Surprisingly, hill-J31 Na channels were threefold more sensitive to rested-state block by lidocaine (402 36 p~M, n = 4-22) than were ~1-~1 Na channels (1,168 34 wM, n = 7-19). In contrast, the inactivated state binding affinities determined at partially depolarized holding potentials ( h ~ 0 . 2 ) were similar (Kd = 16 _ 1 wM, n = 3-9 for hH1-[31 and 12 +2 p~M, n = 4-11 for W1-[31). Lidocaine produced more use-dependent block of peak hill-J31 Na current elicited by trains of short(10 ms) or long(1 s) duration step depolarizations (0.5 Hz, 2 0 mV) than of wl-131 Na current. During exposure to lidocaine, hill-J31 channels recover f rom inactivation at 100 mV after a prolonged delay (20 ms), while pA-[3x channels begin repriming immediately. The overall time course of recovery f rom inactivation in the presence of lidocaine is much slower in hill-J31 than in pA-13a channels. These unexpected findings suggest that structural differences in the 0L 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. I N T R O D U C T I O N Lidoca ine is used clinically as bo th an an t ia r rhy thmic and a local anesthetic. Its sites o f act ion are Na channe ls in heart , skeletal muscle and nerve. While mic romoAddress correspondence to Eduardo MarbAn, M.D., Ph.D., Division of Cardiology, 844 Ross Building, Johns Hopkins University, 720 N. Rudand Avenue, Baltimore, MD 21205. j. GEN. PHYSIOL. 9 The Rockefeller University Press 9 0022-1295/95/12/1193/17 $2.0