The effects of a piperazine derivative, trimetazidine (1-(2, 3, 4-trimethoxybenzyl) piperazine dihydrochloride) on the frog end-plate membrane were studied. Action and resting membrane potentials and the input resistance of muscle fibers were not affected by trimetazidine (82-165 muM). Under these conditions, the frequency of the miniature endplate potentials was unchanged while its amplitude was slightly decreased. The amplitude of acetylcholine (ACh) potentials were markedly and reversibly decreased after application of trimetazine (82-165 muM). The dose response curve of the end-plate membrane to ACh showed a non-competitive type of blockade. Trimetazidine (165 muM) not only decreased the amplitude of the end-plate currents (EPC) recorded from the glycerinated muscles using a voltage clamp technique, but also drastically shortened its time course. Under these conditions, the falling phase of the EPC became completely voltage insensitive. The equilibrium potential for the EPC slightly shifted to a more negative value in the presence of trimetazine (165 muM). Coefficient of variation of EPC was increased by Trimetazidine (165 mum), indicating a decrease in the quantal content of the EPC. The rate of desensitization of the end-plate to ACh was facilitated and the rate of decrease in EPC amplitude during tetanic stimulation became voltage sensitive by the action of trimetazidine (133 muM). It is concluded that trimetazidine mainly acts on the postsynaptic membrane with a weak presynaptic action. The agent seems to block a step subsequent to the interaction of ACh with its receptor, which presumably involves changes in the ion conductance of the membrane and is responsible for the voltage sensitivity of the response.