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1 Vascular Biology Center, Departments of Surgery, Physiology and Endocrinology, and Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912-2500; and 2 Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois 60064-3500
Experiments were designed to elucidate
the role of endothelin B receptors (ETB) on arterial
pressure and renal function in deoxycorticosterone acetate (DOCA)-salt
hypertensive rats. Male Sprague-Dawley rats underwent uninephrectomy
and were treated with either DOCA and salt (0.9% NaCl to drink) or
placebo. DOCA-salt rats given the ETB-selective antagonist,
A-192621, for 1 wk (10 mg · kg
1 · day1
in the food) had significantly greater systolic arterial pressure compared with untreated DOCA-salt rats (208 ± 7 vs. 182 ± 4 mmHg) whereas pressure in placebo rats was unchanged. In DOCA-salt, but not
placebo rats, A-192621 significantly decreased sodium and water
excretion along with parallel decreases in food and water intake. To
determine whether the response in DOCA-salt rats was due to increased
expression of ETB receptors, endothelin receptor binding
was performed by using membranes from renal medulla. Maximum binding
(Bmax) of [125I]ET-1,
[125I]ET-3, and
[125I]IRL-1620 increased from 227 ± 42, 146 ± 28, and 21 ± 1 fmol/mg protein, respectively, in
placebo rats to 335 ± 27, 300 ± 38, and 61 ± 6 fmol/mg protein,
respectively, in DOCA-salt hypertensive rats. The fraction of receptors
that are the ETB subtype was significantly increased in
DOCA-salt (0.88 ± 0.07) compared with placebo (0.64 ± 0.01). The
difference between [125I]ET-3 and
[125I]IRL-1620 binding is consistent with
possible ETB receptor subtypes in the kidney. These results
indicate that ETB receptors in the renal medulla are
up-regulated in the DOCA-salt hypertensive rat and may serve to
maintain a lower arterial pressure by promoting salt and water excretion.
endothelin B receptors; deoxycorticosterone; hypertension; sodium diet
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