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Differential block of sodium and calcium channels by chlorpromazine in mouse neuroblastoma cells.

1. The effects of chlorpromazine on the voltage‐activated sodium and type I (transient) calcium channels were studied in cultured mouse neuroblastoma cells (N1E‐115) using the whole‐cell patch‐clamp technique. 2. Chlorpromazine (2‐10 x 10(‐6) M) blocked both the sodium channel current and the calcium channel current as carried by Ba2+ in a reversible and dose‐dependent manner. 3. The block was not associated with any change in the time course of the activation and inactivation of the sodium and calcium channel currents. 4. The dose‐response relationships for the block of these channels measured with a holding potential of ‐120 mV indicated a 1:1 binding stoichiometry with apparent dissociation constants of 2.5 +/‐ 10(‐6) M and 1.5 +/‐ 10(‐5) M for the sodium and calcium channels, respectively. 5. The block was dependent on the holding potential for both channel currents. The apparent dissociation constant for the sodium channel was decreased to 0.65 +/‐ 10(‐6) M when the membrane was held at ‐80 mV. The apparent dissociation constant for the calcium channel was decreased to 3.2 +/‐ 10(‐6) M when the membrane was held at ‐60 mV. 6. The steady‐state inactivation curve for the sodium channel was shifted by 12.4 +/‐ 1.8 mV to more negative potentials by exposure to 1 x 10(‐6) M‐chlorpromazine. The inactivation curve for the calcium channel was also shifted by 15.4 +/‐ 3.2 mV to more negative potentials by exposure to 1 x 10(‐5) M‐chlorpromazine. These results indicate a greater affinity of chlorpromazine for the inactivated state of the channels than for the resting state. 7. Chlorpromazine caused a marked use‐dependent block of the sodium channel current, as demonstrated by a cumulative increase of the block during a train of depolarizing pulses. The use‐dependent block was observed even with an interpulse interval as long as 2 s. 8. On the other hand, the block of the calcium channel current did not notably accumulate during a train of depolarizing pulses even when extremely prolonged (1 s) pulses were applied at a very short interpulse interval (200 ms). 9. The marked use dependence of the sodium channel block was due to a very slow repriming of the drug‐bound sodium channels from inactivation, whereas the lack of use dependence of the calcium channel block was due to a rapid repriming of the drug‐bound calcium channels.(ABSTRACT TRUNCATED AT 400 WORDS)