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1 Vascular Biology Center and 2 Departments of Pediatrics, 3 Pharmacology and Toxicology, and 4 Surgery, Medical College of Georgia, Augusta, Georgia 30912-2500; and 5 Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52240
Several disease states, including hypertension, are associated
with elevations in plasma endothelin-1 (ET-1) and variable changes in
vascular contraction to ET-1. The spotting lethal (sl) rat
carries a deletion of the endothelin-B (ETB) receptor gene that prevents expression of functional ETB receptors,
resulting in elevated plasma ET-1. On a normal diet, these rats are
normotensive and thus provide an opportunity to study the vascular
effects of chronically elevated ET-1 in the absence of hypertension.
Studies were performed in rats homozygous for the ETB
deficiency (sl/sl; n = 8) and in
transgenic rats heterozygous for the ETB deficiency (sl/+; n = 8). Plasma ET-1 was elevated in
sl/sl rats (3.85 ± 0.55 pg/ml) compared
with sl/+ rats (0.31 ± 0.11 pg/ml). Mean arterial
blood pressure in conscious unrestrained sl/sl
and sl/+ rats was 101 ± 5 and 107 ± 6 mmHg,
respectively. Concentration-dependent contractions to ET-1
(10
11-108 M) were reduced in
mesenteric small arteries (150-250 µm) from sl/sl rats, as indicated by an ~10-fold
increase in EC50. A selective ETA antagonist,
A-127722 (30 nM), abolished contraction to ET-1 in both groups, whereas
a selective ETB antagonist had no effect. Also,
ETB agonists (IRL-1620 and sarafatoxin 6c) produced neither contraction nor relaxation in either group, indicating that contraction to ET-1 in this vascular segment was exclusively ETA
dependent. Despite increased plasma ET-1, protein expression of
ETA receptors in membrane protein isolated from mesenteric
small arteries was increased in sl/sl compared
with sl/+ rats, as shown by Western blotting. These results
indicate that, in ETB-deficient rats, ETA-induced contraction is reduced in vessels normally
lacking ETB-mediated effects. Reduced contraction may be
related to elevated plasma ET-1 and occurs in the presence of increased
ETA receptor protein expression, suggesting an uncoupling
of ETA receptor expression from functional activity.
endothelin-1; homozygous ETB-deficient rats; heterozygous ETB-deficient rats; resistance arteries; arterial pressure
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