Effects of antipsychotic drugs on action potential production in skeletal muscle. I. Chlorpromazine and promethazine

Abstract

The effects of chlorpromazine, an antipsychotic phenothiazine, and promethazine, an antihistaminic phenothiazine, on excitability and action potential production in frog's sartorius muscle fibers were studied and compared. Both drugs produced a local anaesthetic effect which developed slowly over 3 to 5 h with lower concentrations (1 to 15 × 10−6 M) and was only partially reversed by exposing the muscles to a drug-free solution for 3 to 4 h. The resting potential and the input resistance of the muscle fibers were unaffected by drug concentrations which reduced the action potential maximum rate of rise, the threshold current of 2-ms injected pulses and the intracellularly measured threshold depolarization. The effects on the action potential were antagonized in an apparently competitive manner by sodium ions. Thus both drugs depressed excitability and the rising phase of the action potential by inhibiting the specific increase in sodium conductance (gNa) which normally follows an adequate stimulus. It was shown that both drugs also inhibited the secondary rise in potassium conductance (gK) which normally occurs during an action potential. Although quantitatively similar, lower concentrations of chlorpromazine (> 15 × 10−6 M) were more potent and higher concentrations (> 15 × 10−6 M) were less potent than promethazine. The qualitatively identical and the quantitatively similar effects of these two drugs would suggest that the antipsychotic effect produced by some of the phenothiazines is unrelated to their effects on action potential production.