Experiments were designed to elucidate the role of endothelin B receptors (ET(B)) on arterial pressure and renal function in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Male Sprague-Dawley rats underwent uninephrectomy and were treated with either DOCA and salt (0.9% NaCl to drink) or placebo. DOCA-salt rats given the ET(B)-selective antagonist, A-192621, for 1 wk (10 mg. kg(-1). day(-1) in the food) had significantly greater systolic arterial pressure compared with untreated DOCA-salt rats (208 +/- 7 vs. 182 +/- 4 mmHg) whereas pressure in placebo rats was unchanged. In DOCA-salt, but not placebo rats, A-192621 significantly decreased sodium and water excretion along with parallel decreases in food and water intake. To determine whether the response in DOCA-salt rats was due to increased expression of ET(B) receptors, endothelin receptor binding was performed by using membranes from renal medulla. Maximum binding (B(max)) of [(125)I]ET-1, [(125)I]ET-3, and [(125)I]IRL-1620 increased from 227 +/- 42, 146 +/- 28, and 21 +/- 1 fmol/mg protein, respectively, in placebo rats to 335 +/- 27, 300 +/- 38, and 61 +/- 6 fmol/mg protein, respectively, in DOCA-salt hypertensive rats. The fraction of receptors that are the ET(B) subtype was significantly increased in DOCA-salt (0.88 +/- 0.07) compared with placebo (0.64 +/- 0.01). The difference between [(125)I]ET-3 and [(125)I]IRL-1620 binding is consistent with possible ET(B) receptor subtypes in the kidney. These results indicate that ET(B) receptors in the renal medulla are up-regulated in the DOCA-salt hypertensive rat and may serve to maintain a lower arterial pressure by promoting salt and water excretion.