Ghrelin, a novel 28 amino-acid peptide hormone, was originally discovered as a centrally-acting orexigenic hormone. Our laboratory has recently demonstrated that ghrelin receptors are present in the kidney in collecting duct cells where they increase ENaC-dependent Na+ reabsorption in normal rats. However, nothing is known about the function of intrarenal ghrelin receptors in SHR. To evaluate this system, uninephrectomized 10-week-old female SHR (N=16) received three cumulative 1 h renal interstitial (RI) infusions of the specific ghrelin receptor antagonist D-LYS-GHRP-6 (4, 6, 8 μg/min; Tocris) following a 1 h control infusion of vehicle 5% dextrose in water (D5W). Rats that received 4 cumulative 1 h RI infusions of D5W served as time controls. Mean arterial pressure values, urine Na+ excretion rates (UNaV), and urine flow rates were determined for each period. Following the RI infusion of D-LYS-GHRP-6, UNaV increased from a baseline value of 0.035 ± 0.004 μmol/min to 0.062 ± 0.011 μmol/min in period 1 (P<0.05), 0.093 ± 0.018 μmol/min in period 2 (P<0.05), and 0.13 ± 0.019 μmol/min in period 3 (P<0.01). Furthermore, RI D-LYS-GHRP-6 infusion increased urine flow rate from a baseline value of 0.002 ± 0.0003 ml/min to 0.005 ± 0.001 ml/min during period 1, 0.006 ± 0.002 ml/min during period 2, and 0.01 ± 0.003 ml/min during period 3 (P<0.05 for all 3 periods). There were no significant changes in either UNaV or urine flow rate in the time controls. Mean arterial pressure responses remained unchanged following the RI infusions, suggesting that all agents were confined to the kidney. These data introduce a potential new therapeutic target for the treatment of sodium and water retention in SHR.