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Block of human voltage‐sensitive Na+ currents in differentiated SH‐SY5Y cells by lifarizine

1 The ability of lifarizine (RS‐87476) to block human voltage‐sensitive Na+ channel currents was studied by use of whole cell patch clamp recording from differentiated neuroblastoma cells (SH‐SY5Y). 2 The Na+ conductance in differentiated SH‐SY5Y cells (24.0 ± 2.4 nS, n = 11) was half‐maximally activated by 10 ms depolarizations to − 37 ± 2 mV and was half‐maximally inactivated by predepolariz‐ pulses of 200 ms duration to − 86 ± 3 mV (n = 11). 3 At low stimulus frequencies (0.1 to 0.33 Hz) voltage‐dependent sodium currents were completely blocked, in a concentration‐dependent manner, by extracellular application of either tetrodotoxin (EC50 = 4 ± 1 nm, n= 12) or by lifarizine (EC50 = 783 ± 67 nm, n = 9). The onset of block by lifarizine (τ = 91 ± 14 s at 10 μm) was considerably slower than that of tetrodotoxin (τ = 16 ± 3 s at 100 nm). 4 Lifarizine (1 μm) reduced the peak sodium conductance in each cell (from 26.4 ± 2.0 nS to 15.1 ± 2.7 nS, n = 4) without changing the macroscopic kinetics of sodium current activation or inactivation (V1/2 = − 35 ± 1 mV and − 87 ± 4 mV respectively, n = 4). Similarly, lifarizine (1 μm) did not affect the reversal potential of the macroscopic sodium current (+ 14 ± 5 mV in control and ‐I‐ 16 ± 2 mV in 1 μm lifarizine; n = 4) or reactivation time‐constant (τ = 14.0 ± 4.4 ms). 5 Block of the sodium channel open state by tetrodotoxin (30 nm) did not prevent the inhibition caused by a subsequent application of lifarizine (3 μm). In contrast the depression caused by lifarizine was readily reversible after pretreatment of cells with the local anaesthetic, lignocaine (10 μm). 6 These data demonstrate that lifarizine is a use‐ and voltage‐dependent antagonist of human voltage‐sensitive sodium currents. The slow kinetics and pharmacology of the block by lifarizine indicate that access of this drug to the channel is more restricted than that of tetrodotoxin and may involve an allosteric site or state of the channel that is also regulated by local anaesthetics.