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1 Department of Pharmacology and Toxicology and 2 Department of Physiology and Endocrinology, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912
Endothelin-1 (ET-1) is thought to play an
important role in the development of deoxycorticosterone acetate
(DOCA)-salt hypertension. Because hypertension is associated with an
increased incidence of coronary artery disease, this study was designed
to determine if coronary vascular contraction to ET-1 is altered in
DOCA-salt hypertensive rats and to determine the effect of chronic
treatment of DOCA-salt rats with the selective
ETA receptor antagonist A-127722. Male Sprague-Dawley rats were divided into four groups: DOCA, Placebo,
DOCA + A-127722, and Placebo + A-127722. A-127722 was administered in
drinking water at a concentration of 8 mg/100 ml. After 3 wk, mean
arterial pressure (MAP) was significantly enhanced in DOCA-salt
compared with Placebo rats. A-127722 significantly inhibited the
increase in MAP. Contraction to ET-1
(10
11 to 3 × 108 M) was measured in
isolated coronary and mesenteric small arteries (200-300 µm,
intraluminal diameter) maintained at a constant intraluminal pressure
of 40 mmHg and was significantly impaired in vessels from DOCA-salt
compared with Placebo rats. Dose-dependent contractions to KCl were
also inhibited in coronary, but only minimally impaired in mesenteric,
arteries of DOCA-salt rats. Inhibition of nitric oxide synthase
activity did not restore contraction to ET-1 in coronary small
arteries. However contractions to ET-1 were enhanced in mesenteric
small arteries. Chronic treatment with A-127722 significantly restored
contraction to ET-1 in coronary, but not in mesenteric, arteries of
DOCA-salt rats. Because ETA
receptor blockade impairs the development of hypertension and improves coronary vascular reactivity, these data indicate that ET-1 plays an
important role in coronary vascular dysfunction associated with
DOCA-salt hypertension.
deoxycorticosterone acetate-salt hypertensive rats; A-127722; nitric oxide; coronary small artery; mesenteric small artery
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