Renal clearance studies were conducted to determine the role of ET(B) receptors in the renal response to big endothelin-1 (big ET-1). Two series of experiments were conducted on Inactin-anesthetized rats to contrast acute pharmacological blockade of ET(B) receptors vs. genetic ET(B) receptor deficiency. In the first series, Sprague-Dawley rats were given either ET(B)-selective antagonist, A-192621, or vehicle (0.9% NaCl) prior to infusion of big ET-1 (10 pmol.kg(-1).min(-1)) for 60 min. A-192621 significantly increased baseline mean arterial pressure (MAP; 102 +/- 4 vs. 141 +/- 6 mmHg, P < 0.05) and urine flow rate (0.5 +/- 0.1 vs. 1.3 +/- 0.2 microl/min, P < 0.05) without any effect on glomerular filtration rate (GFR) or effective renal plasma flow (ERPF). Big ET-1 significantly increased MAP in both groups but to a higher level in rats given antagonist (120 +/- 6 vs. 169 +/- 6 mmHg, P < 0.05). Big ET-1 increased urine flow in control rats but decreased in rats given antagonist. GFR and ERPF were decreased in rats given big ET-1, an effect that was exaggerated by ET(B) blockade. Another series of experiments examined the response to big ET-1 in rats lacking functional renal ET(B) receptors, known as spotting lethal (sl) rats. Surprisingly, rats heterozygous (sl/+) for ET(B) receptor deficiency had a significantly higher baseline MAP compared with homozygous (sl/sl) rats (134 +/- 6 vs. 112 +/- 7 mmHg, P < 0.05), although other variables were similar. Big ET-1 produced no significant change in MAP in either group. Urine flow, GFR, and ERPF were significantly decreased in both groups, although these changes were much larger in sl/sl rats. These experiments indicate that the ET(B) receptor plays an important role in limiting the renal hemodynamic response to big ET-1. Furthermore, the diuretic actions of big ET-1 require a functional ET(B) receptor.