The antifibrillatory drug bretylium and the antiepileptic drug diphenylhydantoin cause an increase in the potential different and in the short-circuit current (SCC) across frog skin when added to the outer surface. The effect of both drugs depends upon the presence of sodium ions in the outer medium and is blocked by the specific sodium channel blocker, amiloride. Quantitative analysis shows that amiloride binds to open as well as closed mucosal sodium channel with the same affinity. The effects of diphenylhydantoin and bretylium differ with respect to their dependence on external pH. The diphenylhydantoin or the bretylium stimulatory effects are additive to the effects of oxytocin. In most cases the diphenylhydantoin and bretylium effects are also additive. It is concluded that the external side of the mucosal Na+ channels contains sites which interact specifically with either bretylium or diphenylhydantoin and thus remove the sodium induced closure of the channels.