Salt-sensitive hypertension in endothelin-B receptor-deficient rats

The role of the endothelin-B receptor (ETB) in vascular homeostasis is cont roversial because the receptor has both presser and depressor effects in vi vo. Spotting lethal (sl) rats carry a naturally occurring deletion in the E TB gene that completely abrogates functional receptor expression. Rats homo zygous for this mutation die shortly after birth due to congenital distal i ntestinal aganglionosis. Genetic rescue of ETBsl/sl rats from this developm ental defect using a dopamine-hydroxylase (DBH)-ETB transgene results in ET B-deficient adult rats. On a sodium-deficient diet, DBH-ETB;ETBsl/sl and DB H-ETB;ETB+/+ rats both exhibit a normal arterial blood pressure, but on a h igh-sodium diet, the former are severely hypertensive. We find no differenc e in plasma renin activity or plasma aldosterone concentration between salt -fed wild-type, DBH-ETB;ETB+/+ or DBH-ETB;ETBsl/sl rats, and acute response s to intravenous L-NAME and indomethacin are similar between DBH-ETB;ETBsl/ sl and DBH-ETB;ETB+/+ rats. Irrespective of diet, DBH-ETB;ETBsl/sl rats exh ibit increased circulating ET-1, and, on a high-sodium diet, they show incr eased but incomplete hypotensive responses to acute treatment an ETA-antago nist. Normal pressure is restored in salt-fed DBH-ETB;ETBsl/sl rats when th e epithelial sodium channel is blocked with amiloride. We conclude that DBH -ETB;ETBsl/sl rats are a novel single-locus genetic model of severe salt-se nsitive hypertension. Our results suggest that DBH-ETB;ETBsl/sl rats are hy pertensive because they lack the normal tonic inhibition of the renal epith elial sodium channel.