Chromaffin cells of the toad were used to investigate the effects of total replacement of extracellular Na+ by monovalent cations or sucrose on secretion of catecholamine (CA). 2. K+, Rb+ or Cs+ in place of Na+ produced an immediate secretory response, which are dependent on extracellular Ca2+ and it was blocked by Co2+. Li+ or choline+ did not affect basal secretion. 3. Isosmotic replacement of Na+ by sucrose caused CA secretion even in the absence of external Ca2+ or in the presence of Ca-channel blockers. 4. Tetraethylammonium decreased the extent of CA release produced by either K+ or Rb+. 5. The secretagogue effect of Na+/K+, Na+/Rb+ or Na+/Cs+ replacement could be explained by a depolarization of the cell membrane, which ultimately will cause Ca2+ influx through voltage-dependent Ca-channels. However, the present results indicate that Na+ may be sufficient but not necessary for CA secretion.