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Salt-sensitive hypertension in endothelin-B receptor–deficient rats
Cheryl E. Gariepy, … , James A. Richardson, Masashi Yanagisawa
Cheryl E. Gariepy, … , James A. Richardson, Masashi Yanagisawa
Published April 1, 2000
Citation Information: J Clin Invest. 2000;105(7):925-933. https://doi.org/10.1172/JCI8609.
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Article

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

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Abstract

The role of the endothelin-B receptor (ETB) 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 ETB 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 ETBsl/sl rats from this developmental defect using a dopamine-—hydroxylase (DBH)-ETB transgene results in ETB-deficient adult rats. On a sodium-deficient diet, DBH-ETB;ETBsl/sl and DBH-ETB;ETB+/+ 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-ETB;ETB+/+ or DBH-ETB;ETBsl/sl rats, and acute responses 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 exhibit increased circulating ET-1, and, on a high-sodium diet, they show increased but incomplete hypotensive responses to acute treatment an ETA-antagonist. Normal pressure is restored in salt-fed DBH-ETB;ETBsl/sl rats when the 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-sensitive hypertension. Our results suggest that DBH-ETB;ETBsl/sl rats are hypertensive because they lack the normal tonic inhibition of the renal epithelial sodium channel.

Authors

Cheryl E. Gariepy, Takashi Ohuchi, S. Clay Williams, James A. Richardson, Masashi Yanagisawa

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Figure 5

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Circulating ET-1 levels and blood pressure response to ETA blockade in D...
Circulating ET-1 levels and blood pressure response to ETA blockade in DBH-ETB;ETB+/+ and DBH-ETB;ETBsl/sl rats. DBH-ETB;ETBsl/sl rats exhibited increased circulating ET-1 levels as measured by sandwich-type enzyme immunoassay (a). The level of dietary sodium did not significantly affect circulating ET-1 levels in DBH-ETB;ETB+/+ rats. However, ETB genotype significantly affected plasma ET-1 levels. a shows a significant increase in plasma ET-1 in DBH-ETB;ETBsl/sl rats (13.2 ± 2.8 pg/mL) compared with DBH-ETB;ETB+/+ rats (2.1 ± 1.8 pg/mL; P < 0.02) on a sodium-deficient deficient diet. On a high-sodium diet, the plasma ET-1 level in DBH-ETB;ETBsl/sl rats (23.9 ± 4.2 pg/mL) was also significantly increased compared with DBH-ETB;ETB+/+ rats (4.4 ± 1.4 pg/ml; P < 0.001). DBH-ETB;ETBsl/sl rats on a high-sodium diet exhibited a significantly increased plasma ET-1 level compared with DBH-ETB;ETBsl/sl rats on a sodium-deficient diet, although diet was not an independent variable affecting plasma ET-1 concentration by 2-way ANOVA. (b) DBH-ETB;ETBsl/sl rats exhibit an increased acute depressor response to ETA blockade with FR139317 (10 mg/kg, intra-arterially) compared with ETB+/+ rats on a high-sodium diet. DBH-ETB;ETBsl/sl rats are significantly hypertensive compared with DBH-ETB;ETB+/+ rats before and after treatment with FR139317. However, the change in MAP in DBH-ETB;ETBsl/sl rats in response to FR139317 (–15 ± 5 mmHg) is significantly greater than in DBH-ETB;ETB+/+ rats (–3 ± 2 mmHg; AP = 0.01).

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