Entamoeba histolytica (axenic strain HM1-IMSS), a cytolytic enteric pathogen, kills target Chinese hamster ovary cells in two discrete steps: (1) carbohydrate-specific adherence of amoebae to target cells, followed by (2) cytolysis of adherent target cells. Both steps require intact amoebic microfilament function. The effects of the fast Na+ channel blocker tetrodotoxin and the slow Na+-Ca++ channel blockers verapamil (10(-5) M) and bepridil (10(-5) M) on amoebic killing were evaluated. Verapamil and bepridil both decreased amoebic killing (P less than 0.001); tetrodotoxin had no effect. Bepridil, but not verapamil, inhibited amoebic adherence at 37 C (P less than 0.001). Both verapamil and bepridil inhibited amoebic lysis of cells after adherence occurred (P less than 0.001). Verapamil protected target cells from lysis by amoebae (P less than 0.005), whereas bepridil reduced the capacity of amoebae to kill Chinese hamster ovary cells (P less than 0.001). These findings suggest that changes in transmembrane ion flux in both the amoeba and the target cell are involved in amoebic killing of target cells.