Dopamine-1 (DA1) receptors in the renal tubules may be involved in the regulation of sodium homeostasis. To test this hypothesis, fenoldopam, a selective DA1 agonist, was infused at 0.05 microgram/kg/min i.v. in 16 normal male subjects in metabolic balance at 300 or 10 meq sodium. Renal function studies were performed by standard p-aminohippurate, inulin, and lithium clearances for three periods: 1) precontrol (2 hours), 2) experimental (3 hours), and 3) postcontrol (2 hours). DA1 receptor stimulation in sodium-loaded individuals increased the following parameters during the experimental period: urine flow rate, from 12.5 +/- 0.4 to 15.5 +/- 0.5 ml/min (p less than 0.05); urinary sodium excretion, from 309 +/- 12 to 489 +/- 18 mu eq/min (p less than 0.001); renal plasma flow, from 631 +/- 19 to 717 +/- 21 ml/min (p less than 0.005); fractional sodium excretion, from 2.2 +/- 0.1% to 3.4 +/- 0.1% (p less than 0.001); fractional lithium excretion, from 26.2 +/- 0.7% to 32.1 +/- 0.8% (p less than 0.005); and distal sodium load, from 10.7 +/- 0.4 to 13.8 +/- 0.5 ml/min (p less than 0.05). The increase in fractional sodium excretion was greater than that of fractional lithium excretion (p less than 0.0001). Distal sodium reabsorption decreased from 78.3 +/- 0.8% to 73.2 +/- 1.1% but the change was not statistically significant. In contrast, sodium-depleted subjects exhibited no significant changes except in renal plasma flow, which rose from 550 +/- 13 to 625 +/- 17 ml/min (p less than 0.0001). Glomerular filtration rate remained unchanged through the entire study. These results indicate that diuretic and natriuretic responses are mediated by DA1 receptors at both proximal and distal tubular sites. Attenuation of the DA1 natriuretic response during sodium depletion suggests a direct inhibition of cellular DA1 mechanisms in the renal tubule or recruitment of nondopaminergic compensatory homeostatic mechanisms within the kidney.