Gariepy C E, Ohuchi T, Williams S C, Richardson J A, Yanagisawa M
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
J Clin Invest. 2000 Apr;105(7):925-33. doi: 10.1172/JCI8609.
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.
内皮素B受体（ET(B)）在血管稳态中的作用存在争议，因为该受体在体内兼具升压和降压作用。斑点致死（sl）大鼠的ET(B)基因存在自然缺失，这完全消除了功能性受体的表达。该突变的纯合子大鼠出生后不久因先天性远端肠道神经节缺失而死亡。使用多巴胺-β-羟化酶（DBH）-ET(B)转基因从这种发育缺陷中对ET(B)(sl/sl)大鼠进行基因拯救，可得到ET(B)缺陷的成年大鼠。在低钠饮食下，DBH-ET(B);ET(B)(sl/sl)大鼠和DBH-ET(B);ET(B)(+/+)大鼠的动脉血压均正常，但在高钠饮食下，前者会出现严重高血压。我们发现，在高盐喂养的野生型、DBH-ET(B);ET(B)(+/+)或DBH-ET(B);ET(B)(sl/sl)大鼠之间，血浆肾素活性或血浆醛固酮浓度没有差异，并且DBH-ET(B);ET(B)(sl/sl)大鼠和DBH-ET(B);ET(B)(+/+)大鼠对静脉注射L-精氨酸甲酯（L-NAME）和吲哚美辛的急性反应相似。无论饮食如何，DBH-ET(B);ET(B)(sl/sl)大鼠的循环内皮素-1（ET-1）都会增加，并且在高钠饮食下，它们对ET(A)拮抗剂急性治疗的降压反应增强但不完全。当用氨氯地平阻断上皮钠通道时，高盐喂养的DBH-ET(B);ET(B)(sl/sl)大鼠的血压恢复正常。我们得出结论，DBH-ET(B);ET(B)(sl/sl)大鼠是一种新型的严重盐敏感性高血压单基因遗传模型。我们的结果表明，DBH-ET(B);ET(B)(sl/sl)大鼠患高血压是因为它们缺乏对肾上皮钠通道的正常张力性抑制。
