Significant proximal tubular responses to exogenous dopamine require 0.1 to 10 mumol/L concentrations but endogenous peritubular dopamine and DOPA concentrations are in the picomolar to nanomolar range. Dopamine concentration approaches micromolar levels within proximal tubular cells and their brush borders, as a result of DOPA decarboxylation and secretion, and in collecting duct fluid, as a result of tubular fluid absorption. Thus dopamine probably acts either within the proximal tubule cell or brush border or from the collecting tubular lumen. DOPA and Na+ uptake are coupled; dopamine uptake is linked to intracellular electrical potential and its secretion to H+ counter-transport; therefore alterations in proximal tubular Na+ and H+ transport influence dopamine excretion. Haloperidol and SCH 23390 block dopamine excretion, therefore dopamine antagonists may inhibit tubular dopamine responses by lowering intracellular dopamine concentration as well as by receptor blockade. Evidence for an intracellular site of dopamine action can be deduced from the inhibitory effect of DOPA on oxygen consumption and 86Rb uptake in proximal tubule cells. We have confirmed these findings in isolated proximal tubule cells but not in proximal tubule fragments. The discrepant responses may be due to the fact that isolated cells loose their polarity while tubule fragments remain polarized. Dopamine inhibition of proximal tubular Na+, K(+)-ATPase is not reproduced by single dopamine agonists or inhibited by dopamine antagonists. Dopamine effects which are not linked to known dopamine receptors may be the result of redox cycling. Micromolar dopamine oxidizes sulfhydryl groups which may modify enzyme structure and activate protein kinase C.