This study describes for the first time an experimental system for the extraneuronal transport mechanism of noradrenaline (uptake 2) which is based on a clonal cell line (Caki-1). Caki-1 cells were originally derived from a human renal cell carcinoma. The conclusion that these cells express uptake 2 is supported by several experimental findings. (1) The initial rate of 3H-noradrenaline uptake in Caki-1 cells is saturable, the Km being 450 mumol/l. (2) Inhibitors of uptake 2 such as corticosterone (1 mumol/l) and O-methyl-isoprenaline (100 mumol/l) largely inhibit 3H-noradrenaline uptake in Caki-1 cells. Whereas inhibitors of the neuronal transport mechanism for noradrenaline (uptake 1) such as desipramine (1 mumol/l) and cocaine (10 mumol/l) do not reduce it. (3) Depolarization of Caki-1 cells by the elevation of extracellular potassium inhibits 3H-noradrenaline uptake. (4) There is a highly significant correlation between the Ic50's of various compounds for the inhibition of 3H-noradrenaline uptake in Caki-1 cells and rabbit aorta known to possess uptake2. Interestingly enough, uptake 2 in Caki-1 cells and rabbit aorta is inhibited by cimetidine, quinidine and procainamide which are substrates of the renal transport mechanism for organic cations. Moreover, 3H-cimetidine is shown to be a substrate of uptake 2 in the isolated perfused rat heart. These results indicate a striking similarity between uptake 2 and the renal transport mechanism for organic cations.