Experiments were conducted to determine the effect of chronic ETA receptor blockade on mean arterial pressure (MAP) and renal function in the DOCA-salt hypertensive rat. Male, SD rats underwent a right nephrectomy and subcutaneous implantation of a time-release pellet containing deoxycorticosterone acetate (DOCA). DOCA rats were also given saline to drink. Control rats were implanted with a placebo pellet and given tap water to drink. Four groups of rats were studied: DOCA (D), placebo (P), DOCA + A-127722 (D+A), and placebo + A-127722 (P+A). The ETA-selective antagonist, A-127722, was placed in the drinking solution at a concentration of 8 mg/100 ml. Rats were maintained in metabolism cages to monitor food and water intake and excretory function. After 3 weeks, a carotid artery catheter was implanted one day prior to determining MAP in conscious rats. MAP was significantly elevated in D rats. A-127722 significantly reduced MAP in D+A rats but not in P+A rats. Creatinine clearance, used as a measure of GFR, was significantly reduced in D rats compared to P rats. A-127722 had no effect on creatinine clearance in either D+A or P+A rats. These data support a role for ET-1 in mediating hypertension but not the renal dysfunction associated with DOCA-salt. Group p P+A D D+A MAP (mmHg) 126 ±5 126 ±7 198 ±8 * 152 ±8 * 1 Ccreat (L/day) 1.9 ±0.1 1.7 ±0.2 07 ±00/1 * 0.7 ±0.1 * * P<0.05 vs. P. 1 P<0.05 vs. D. MAP, mean arterial pressure; Ccreat, creatinine clearance; P, placebo; D, DOCA-salt; A, A-127722.