Experiments were conducted to determine the influence of ETB receptors in the control of renal medullary function. The acute relation between renal perfusion pressure (RPP) and natriuresis was examined in anesthetized rats treated with the ETB antagonist A-192621 (10 mg/kg IV). In A-192621-treated rats, sodium excretion (UNaV) was 0.4±0.1, 0.6±0.3, and 2.7±0.5/ μmol/min at RPP of 80±1, 107±1, and 144±5 mm Hg, respectively. In control rats, UNaV averaged 0.8±0.4, 3.4±1.2, and 8.1±1.7 μmol/min at RPP of 77±2, 115±5, and 137±3 mm Hg, respectively. For normal and high RPP, UNaV was significantly lower in A-192621-treated rats compared with control rats. Additional experiments determined the effects of Big ET-1 (10 μmol/kg per minute) on intrarenal blood flow. Medullary blood flow (MBF) and cortical blood flow were measured in anesthetized rats by single-fiber, laser Doppler flowmetry. Cortical blood flow significantly decreased in response to Big ET-1 in rats on a normal or high salt diet. Big ET-1 significantly increased MBF in rats on a high salt diet, whereas there was no change in MBF in rats on a normal salt diet. These results demonstrate that medullary vasodilation produced by Big ET-1 is more prominent in rats on a high salt diet and are consistent with a contribution of ETB-mediated events in the natriuretic response to high salt intake. Taken together, these findings support the hypothesis that endothelin plays an important role in regulating sodium excretion through activation of ETB receptors.