To examine whether K+ affects the potency of inhibitors of neuronal uptake, experiments were carried out in the rat vas deferens after pretreatment of the animals with reserpine and after inhibition of monoamine oxidase and catechol-O-methyltransferase. Initial rates of the neuronal uptake of 3H-noradrenaline and IC50 values for uptake inhibition by desipramine, cocaine and (-)metaraminol were determined in the presence of various concentrations of external K+ (5-45 mmol/l), both at 100 mmol/l Na+ and 50 mmol/l Na+. When measured at the 3H-noradrenaline concentration used to determine IC50 values (0.024 mumol/l), neuronal uptake was progressively impaired by increasing K+ concentrations at 50, but not at 100 mmol/l Na+. Neither at 100 mmol/l Na+ nor at 50 mmol/l Na+ was there any consistent, concentration-dependent effect of K+ on the IC50 values of desipramine, cocaine and (-)metaraminol. The analysis of the saturation kinetics of 3H-noradrenaline uptake (determined in the presence of 50 mmol/l Na+ at 5 mmol/l K+ or 45 mmol/l K+) showed that high K+ concentrations inhibit neuronal uptake by decreasing Vmax without any change in Km. The results indicate that K+ does not competitively interact with Na+ at sites on the noradrenaline carrier which mediate the transport-stimulating properties of Na+. Hence, the inhibition of neuronal uptake produced by high K+ concentrations is probably due to membrane depolarization which simply reduces Vmax.