We have examined the effects of various calcium channel blockers on stimulation-induced changes in end-plate potential (EPP) amplitude at the frog neuromuscular junction. We found that the addition of small concentrations (1-10 microM) of Cd2+ to the low calcium bathing Ringer reduced both the control EPP amplitude and the increase in EPP amplitude that normally occurs during repetitive stimulation under low quantal conditions. These effects of Cd2+, which developed rapidly following its addition to the bathing solution and were equally rapidly reversed, resulted from changes in the amount of transmitter released from the nerve terminal. The major effect of Cd2+ appeared to be on the facilitation and augmentation components of increased release. Cd2+ had little or no effect on potentiation of release. The other divalent cations tested, Zn2+, Co2+, and Ni2+, also decreased both control EPP amplitude and the stimulation-induced increase in EPP amplitude, but higher concentrations (> 100 microM) of these cations were required. The order of effectiveness in reducing stimulation-induced increases in EPP amplitude was: Cd2+ >>> Co2+,Zn2+ > Ni2+. The organic calcium channel blockers verapamil (20-100 microM) and nimodipine (20-50 microM) had little effect on stimulation-induced increases in EPP amplitude. The results of this study are consistent with previous suggestions that the different components of increased release represent different mechanisms. Furthermore, if Cd2+ is acting by reducing Ca2+ entry into the nerve terminal, then these results suggest that facilitation and augmentation are dependent in some way on Ca2+ entry.