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The ability of local anesthetics to reduce the amplitude of compound action potentials (CAP) of frog sciatic nerve was examined in the absence and presence of agents that selectively block K+ channels. In the presence of Iidocaine concentrations that inhibit the CAP by about 20% at low frequencies of stimulation (1 per min, “tonic inhibition‘’), the addition of the K+-channel blocker tetraethylammonium ion (TEA, 12 mM) increased this inhibition by another 15%. Furthermore, the use-dependent inhibition induced by lidocaine at higher stimulation frequencies (5–20 Hz, “phasic inhibition‘’) was markedly enhanced by TEA: at 20 Hz it increased from 35% with lidocaine alone to 63% with lidocaine plus TEA. A comparable potentiation was rendered by 3,4-diaminopyridine (1 mM), a different K+-channel blocker. Similarly, phasic inhibition by bupivacaine also was enhanced by TEA. The K+-channel blockers alone slightly depolarized the resting membrane, broadened and elevated the CAP, produced no phasic inhibition, and, during repetitive stimulation, resulted in a less negative steady-state repolarization potential than at rest. Both the broadening of CAP and the depolarizing actions of K+-channel blockers increased the presence of open and inactivated states of the neuronal Na+ channels, and thereby enhanced the binding of local anesthetic. The inhibitory actions of saxitoxin, a Na+-channel blocker that binds equally well to all channel states, were not potentiated by TEA.