Abstract

Effects of chlorpromazine on the giant axon of the squid were studied to establish the manner by which it blocks excitability. The axon, under current and voltage-clamp conditions, was perfused externally or internally with chlorpromazine at a concentration of 1 x 10^-5 M. At normal pH conditions, chlorpromazine blocks the action potential without affecting the resting potential, after external or internal application. Under voltage-clamp conditions, both the transient sodium current and the steady-state potassium current are reduced by external application of chlorpromazine whereas the transient current is predominantly blocked by internal application. Elevating the pH on either side of the axonal membrane results in reversal of the block induced by chlorpromazine whether introduced internally or externally. Further block is subsequently reestablished by lowering the pH of time system, without further drug addition and after a prolonged period of drug-free perfusion. It is concluded that chlorpromazine irreversibly binds to the axonal membrane regardless of the pH and the blockage is exerted by its cationic form on either side of the membrane.