The present study was conducted to test the hypothesis that high salt intake would increase the diuretic and natriuretic effects of renal medullary ETB receptor stimulation in vivo. Two groups of male Sprague Dawley (SD) rats were compared; after being fed normal (0.3%) and high salt (4%) diet for 7 days. Rats were anesthetized and a catheter implanted in the renal medulla for interstitial infusion along with a ureteral catheter for urine collection. An adjustable occluder was placed around the aorta proximal to the left renal artery to maintain renal perfusion pressure throughout the protocol. After equilibration and two 20 min control periods, the urine flow (UV) and sodium excretion (UNaV) responses to medullary infusion of a low dose of the ETB receptor agonist sarafotoxin S6c (0.15 μg/kg/h) were determined over an 80 min infusion period. Intramedullary infusion of a relatively low dose of S6c (0.15 μg/kg/h) markedly increased the urine flow and sodium excretion in the high salt treated rats (UV: 5.6±0.7 to 30.7±3.1 μl/min; UNaV: 1.1±0.2 to 2.2±0.3 μmol/min; n=9), but not in the normal salt treated rats (UV: 8.6±2 to 11.6±1.9 μl/min; UNaV 0.5±0.1 to 0.5±0.1 μmol/min; n=8). We conclude that high salt intake enhances the diuretic and natriuretic effects of ETB receptor stimulation in vivo consistent with a role for the ETB receptor in maintaining fluid‐electrolyte balance.