45Ca washout from ventricles of the bullfrog was followed through an automated technique previously described. Lanthanum decreased the fractional rate of loss of 45Ca (by 67% at the saturating concentration, 1 mM, for this effect of the trivalent cation). In contrast, both manganous and nickel ions decreased the fractional rate of loss of 45Ca in 21 of the 30 ventricles studied. In the remainder of the experiments these ions increased this rate. This augmentation of the rate of 45Ca efflux by manganese and nickel could be converted consistently to an inhibition by experimental maneuvers known to increase the intracellular concentration of sodium-potassium-free washout solution, dihydroouabain. These results are consistent with the hypothesis that manganese and nickel increase 45Ca efflux through a process of sarcolemmal manganese-calcium (or nickel-calcium) exchange, operating through the sodium-calcium exchanger. Support for this interpretation was obtained in the further observation that the rate of loss of radioactive nickel from 63Ni-loaded ventricles was monotonically related to the extracellular concentration of calcium. Thus the augmenting effect of the divalent cations on 45Ca efflux appears to be mediated by the sodium-calcium exchanger. That the inhibitory effect arises from an action of the cations on the ATP-dependent component of 45Ca efflux is indicated by the fact that it disappears after vigorous ATP depletion in the presence of cyanide and 2-deoxy-D-glucose.