SUMMARY: The short-circuit current (SCC, sodium transport) across the isolated toad urinary bladder was increased by the presence of 10−4m-Mn2+ at the serosal but not at the mucosal surface. Magnesium did not have this effect. Zinc (10−4m) decreased the SCC. Neither Mn2+ nor Zn2+ altered the SCC at a concentration of 10−5m. Oxytocin stimulated sodium transport across the bladder and this response was reduced by 10−4 but not by 10−5m-Mn2+. Zinc (10−5m) nearly abolished the effect of oxytocin. Normal osmotic permeability of the bladder to water was unaffected by 10−4m-Mn2+ or Zn2+. Oxytocin increased the osmotic permeability of the bladder to water and this response was strongly inhibited by 10−4 and 10−5m-Mn2+ at the serosal but not at the mucosal surface. Magnesium did not have this effect. Zinc (10−4 to 10−6m) similarly reduced this effect of oxytocin but at a concentration of 10−4m also acted at the mucosal surface. The antagonistic effect of Mn2+ on the action of oxytocin on osmotic permeability was not reversible and was non-competitive. Zn2+ was also found to be a non-competitive antagonist of oxytocin but the antagonism was reversible. The increase in osmotic permeability of the bladder to water by the addition of cyclic AMP was unaffected by Mn2+. In contrast Zn2+ reduced the effects of cyclic AMP on both osmotic permeability and SCC. It is suggested that Mn2+ uncouples processes linking the interaction of oxytocin with the formation of cyclic AMP in the bladder while Zn2+ acts at a stage subsequent to the formation of the nucleotide, possibly on the effector mechanisms themselves.