In the preceding manuscript (Zhao, H., Xu, X., Diaz, J., and Muallem, S. (1995) J. Biol. Chem. 270, 19599-19605), we described a Kout(+)-dependent H+/HCO3- and Na+ influx pathway in the luminal membrane of salivary duct cells. In the present studies, we further characterized this pathway to show that the Kout(+)-dependent Na+ influx was not mediated by the luminal amiloride-sensitive Na+ channel, the Na+/H+ exchangers, or any electroneutral or conductive Cl(-)-dependent transport pathway. Thus, K+ efflux probably maintained electroneutrality during Na+ influx induced by removal of Kout+. Accordingly, Na+ influx was largely inhibited by 2.5mM external Ba2+. The K+ site of the Kout(+)-dependent Na+ influx showed the selectivity sequence Cs+ > K+ > NH4+ >> > Li+ which is different from that of several known K+ channels. More importantly, Na+ influx is 50% inhibited at about 20 mM Kout+, and significant Na+ influx occurred even at 80 mM Kout+. This is a critical property for the pathway to play a role in Na+ reabsorption and K+ secretion by the duct. The large Na+ influx in resting duct cells is matched by high activity of the ductal Na+ pump which is about 8-fold faster than that of acinar cells. Stimulation of submandibular ducts with various agonists increased [Na+]i in an agonist-specific manner. The parasympathetic agonist epinephrine was more effective than isoproterenol and sympathetic agonist carbachol. The use of various inhibitors of Na+ and K+ transporters suggests that different pathways mediate Na+ influx in stimulated acinar and duct cells of the gland. In duct cells, Na+ influx was inhibited only by extracellular Cs+ and Ba2+. The overall findings support a significant role for the Kout(+)-dependent pathway(s) in Na+ reabsorption and K+ and HCO3- secretion and explain several features of transepithelial electrolyte transport by salivary ducts.