The effect of forskolin on voltage-activated Na + and K + currents in nodes of Ranvier from the toad, Bufo marinus, has been examined using the vaseline-gap voltageclamp technique. Peak Na + currents (INa) were reduced by 35 % and the rate of decline of Na + current during continuous depolarization was accelerated following treatment with 450 gM forskolin. However, the voltage-dependence of steady-state inactivation as well as the rate of recovery from fast inactivation remained unchanged. Upon repetitive depolarization at 1-10 Hz, a further inhibition of INa (~ 60%) was observed. This use-dependent or phasic inhibition recovers slowly at -80mV (~ 13 s) and had a voltage-dependence like that of activation of the Na conductance. Near maximal steady-state phasic inhibition occurred with depolarizing pulse durations of only 4 ms, consistent with a direct involvement of the open Na + channel in the blocking process. Inhibition of the delayed K + current (IK) was characterized by a concentration-dependent reduction in steady-state current amplitude (ICs0 ~ 80 ~tM) and a concentration-independent acceleration of current inactivation. A similar inhibition of IK was obtained with 1,9dideoxyforskolin, a homolog which does not activate adenylate cyclase (AC). The results suggest that the inhibition of IK and perhaps IN, follows directly from drug binding and is not a consequence of AC activation.