The effects of guanidine and dimethyl guanidine were studied on current- and voltage-clamped nodes of Ranvier, to determine the electrophysiological basis for the guanidine-induced increase in neurotransmitter release. When added to the external solution, guanidine produced positive shifts of K and Na conductance-voltage curves. As a consequence, we observed a decrease of ionic flux through K channels, as well as through Na channels, and the resultant prolongation of the action potential. In addition, guanidine slowed down the time course of K current activation and reduced the percentage of inactivated Na channels. The main effect of guanidine is thus to induce depolarizing shifts of the potential dependence of K and Na channel gating parameters. Guanidine, like divalent cations, may alter the density of fixed negative charges on the outside membrane surface. The results of the action of dimethyl guanidine imply that, in addition to possible unspecific screening of the negative surface charges by cations, some specific interactions are involved. In conclusion, the prolongation of the action potential attributable to the effect of guanidine on external surface charges might contribute to the action of the drug in facilitating transmitter release by allowing the entry of more Ca ions into nerve endings.