FUNCTIONAL CONSEQUENCES OF LIDOCAINE BINDING TO SLOW-INACTIVATED SODIUM-CHANNELS

Na channels open upon depolarization but then enter inactivated states from which they cannot readily reopen. After brief depolarizations, n ative channels enter a fast-inactivated state from which recovery at h yperpolarized potentials is rapid (<20 ms). Prolonged depolarization i nduces a slow-inactivated state that requires much longer periods for recovery (>1 s). The slow-inactivated state therefore assumes particul ar importance in pathological conditions, such as ischemia, in which t issues are depolarized for prolonged periods. While use-dependent bloc k of Na channels by local anesthetics has been explained on the basis of delayed recovery of fast-inactivated Na channels, the potential con tribution of slow-inac- tivated channels has been ignored. The princip al (alpha) subunits from skeletal muscle or brain Na channels display anomalous gating behavior when expressed in Xenopus oocytes, with a hi gh percentage entering slow-inactivated states after brief depolarizat ions. This enhanced slow inactivation is eliminated by coexpressing th e alpha subunit with the subsidiary beta(1) subunit. We compared the l idocaine sensitivity of or subunits expressed in the presence and abse nce of the beta(1) subunit to determine the relative contributions of fast-inactivated and slow-inactivated channel block. Coexpression of b eta(1) inhibited the use-dependent accumulation of lidocaine block dur ing repetitive (1-Hz) depolarizations from -100 to -20 mV. Therefore, the time required for recovery from inactivated channel block was meas ured at -100 mV. Fast-inactivated (alpha + beta(1)) channels were most ly unblocked within 1 s of repolarization; however, slow-inactivated ( alpha alone) channels remained blocked for much longer repriming inter vals (>5 s). The affinity of the slow-inactivated state for lidocaine was estimated to be 15-25 mu M, versus 24 mu M for the fast-inactivate d state. We conclude that slow-inactivated Na channels are blocked by lidocaine with an affinity comparable to that of fast-inactivated chan nels. A prominent functional consequence is potentiation of use-depend ent block through a delay in repriming of lidocaine-bound slow-inactiv ated channels.