The ionic composition of the medium can influence the actions of many pharmacological agents. We report here our studies of the effects of the extracellular sodium concentration on blockade of calcium-permeable ion channels of AMPA receptors by the cationic phenylcyclohexyl derivative IEM-1925. Experiments were performed using native receptors from striatal giant interneurons isolated from rat brain slices. Recordings were made by whole-cell patch voltage clamping. Replacement of some of the extracellular sodium with sucrose was found to increase the blocking action of IEM-1925. This effect depended on the membrane potential, increasing on hyperpolarization. Analysis of the kinetics of the interaction of IEM-1925 with channels showed that decreases in the extracellular sodium concentration had no effect on the stability of blocker-channel complexes, increases in blockade occurring because of increases in the association rate constant. These results lead to the conclusion that current-carrying sodium ions complete with the blocking IEM-1925 cation for the binding site in the channel.