A comparison of the effectiveness of the trivalent cation, lanthanum (La3+) relative to Ca2+ in causing catecholamine release from bovine chromaffin cells has been made, together with a determination of the pathway by which La3+ enters these cells. In chromaffin cells maintained in tissue culture and permeabilised with digitonin, both La3+ and Ca2+ caused 3H release from cells preloaded with [3H]-noradrenaline; La3+ and Ca2+ caused similar maximal release but the EC50 for La3+ was an order of magnitude less than that for Ca2+. At maximal release caused by either La3+ or Ca2+ (approximately 14% of cell 3H content in 15 min), the other cation caused a small, but significant, further release. At submaximal effective concentrations the effects of the two cations were exactly additive. Using 3H release as an indicator of cytosolic La3+, its route of entry into intact chromaffin cells was investigated. With La(3+)-containing medium there was no release evoked by nicotine or by K(+)-depolarisation indicating that La3+ does not enter either via the nicotinic receptor linked ion channel or via voltage-sensitive (Ca2+) channels. However, in sodium-loaded chromaffin cells (ouabain incubation in Ca(2+)-free medium for 15 min) exposure to bathing media containing either Ca2+ or La3+ caused 3H release. La3+ (0.1 mM) caused a release similar in magnitude to that caused by Ca2+ (about 1 mM). La3+ at low concentrations had an additive (0.1 mM La3+) or synergistic (0.25-0.45 mM La3+) action with Ca2+ (< 3.6 mM) on 3H release. At higher concentrations (> 0.9 mM) the effects of La3+ predominated and prevented the expected effects of Ca2+. In other experiments, La3+ (1 mM) blocked export of 45Ca2+ via both Nao-dependent and independent pathways, i.e. sodium-calcium exchange and the calcium pump. The results indicate that La3+ can enter bovine chromaffin cells via the Nai/Cao exchange pathway independently of, or together with, Ca2+ but, that concentrations above 0.9 mM block the influx or efflux of Ca2+. However, Ca2+, even at 3.6 mM, did not block the influx of La3+. The results further indicate that, within chromaffin cells, La3+ is at least as effective as Ca2+ in triggering catecholamine release and maintaining prolonged release. La3+ also appears to act cooperatively with Ca2+ at the release pathway.