The role of the endothelin-B receptor (ET_B) in vascular homeostasis is controversial because the receptor has both pressor and depressor effects in vivo. Spotting lethal (sl) rats carry a naturally occurring deletion in the ET_B gene that completely abrogates functional receptor expression. Rats homozygous for this mutation die shortly after birth due to congenital distal intestinal aganglionosis. Genetic rescue of ET_B^sl/sl rats from this developmental defect using a dopamine-—hydroxylase (DBH)-ET_B transgene results in ET_B-deficient adult rats. On a sodium-deficient diet, DBH-ET_B;ET_B^sl/sl and DBH-ET_B;ET_B^+/+ rats both exhibit a normal arterial blood pressure, but on a high-sodium diet, the former are severely hypertensive. We find no difference in plasma renin activity or plasma aldosterone concentration between salt-fed wild-type, DBH-ET_B;ET_B^+/+ or DBH-ET_B;ET_B^sl/sl rats, and acute responses to intravenous L-NAME and indomethacin are similar between DBH-ET_B;ET_B^sl/sl and DBH-ET_B;ET_B^+/+ rats. Irrespective of diet, DBH-ET_B;ET_B^sl/sl rats exhibit increased circulating ET-1, and, on a high-sodium diet, they show increased but incomplete hypotensive responses to acute treatment an ET_A-antagonist. Normal pressure is restored in salt-fed DBH-ET_B;ET_B^sl/sl rats when the epithelial sodium channel is blocked with amiloride. We conclude that DBH-ET_B;ET_B^sl/sl rats are a novel single-locus genetic model of severe salt-sensitive hypertension. Our results suggest that DBH-ET_B;ET_B^sl/sl rats are hypertensive because they lack the normal tonic inhibition of the renal epithelial sodium channel.