DISTINCT LOCAL-ANESTHETIC AFFINITIES IN NA+ CHANNEL SUBTYPES

Lidocaine is a widely used local anesthetic and antiarrhythmic drug th at is believed to exert its clinically important action by blocking vo ltage-gated Na+ channels. Studies of Na+ channels from different speci es and tissues and the complexity of the drug-channel interaction crea te difficulty in understanding whether there are Na+ channel isoform s pecific differences in the affinity for lidocaine. Clinical usage sugg ests that lidocaine selectively targets cardiac Na+ channels because i t is effective for the treatment of arrhythmias with few side effects on muscle or neuronal channels except at higher concentrations. One po ssibility for this selectivity is an intrinsically higher drug-binding affinity of the cardiac isoform. Alternatively, lidocaine may appear cardioselective because of preferential interactions with the inactiva ted state of the Na+ channel, which is occupied much longer in cardiac cells. Recombinant skeletal muscle (hSkM1) and cardiac sodium channel s (hH1) were studied under identical conditions, with a whole-cell vol tage clamp used to distinguish the mechanisms of lidocaine block. Toni c block at high concentrations of lidocaine (0.1 mM) was greater in hH 1 than in hSkM1. This was also true for use-dependent block, for which 25-mu M lidocaine produced an inhibition in hH1 equivalent to 0.1 mM in the skeletal muscle isoform. Pulse protocols optimized to explore i nactivated-state block revealed that hSkM1 was five to eight times les s sensitive to block by lidocaine than was hH1. The results also indic ate that relatively more open-state block occurs in hSkM1. Thus, the c ardiac sodium channel is intrinsically more sensitive to inhibition by lidocaine.