Procaine, a tertiary amine, has previously been shown to stimulate reversibly transepithelial Na transport across frog skin after application from the epithelial side. In the present study with intracellular recording from principal, i.e. amiloride-sensitive cells, we demonstrate that the stimulation results from increase in apical membrane Na permeability. A second effect of procaine (10-25 mmol/l) in the outside perfusion solution is a reversible increase of transepithelial conductance which drastically exceeds the predicted response of the transcellular Na pathway. It requires presence of chloride on the epithelial side and depends on the non-ionized molecule of procaine. Abolition of apical membrane Na uptake by amiloride or Na-free mucosal incubation decreases the magnitude but does not prevent the stimulatory effect of procaine. The origin of this gain in conductance from stimulation of a Cl-specific pathway is demonstrated by a highly significant correlation between the increases in electrically determined tissue conductance and partial Cl conductance, obtained from measurements of influx and efflux of Cl-36. Measurements with microelectrodes indicate that the stimulated Cl-specific pathway is distinct from the principal cells. Since procaine activates a conductive pathway with similar response pattern as spontaneously existing Cl conductance, it might be a valuable tool for investigating mode and way of Cl movement across epithelial tissues.