title: Coronary vascular reactivity is improved by endothelin A receptor blockade in DOCA-salt hypertensive rats.
abstract: 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 x 10(-8) M) was measured in isolated coronary and mesenteric small arteries (200-300 micron, 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.
authors.affiliation: Department of Pharmacology and Toxicology, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Giulumian
authors.forename: D M
authors.initials: DM
authors.lastname: Pollock
authors.forename: N
authors.initials: N
authors.lastname: Clarke
authors.forename: L C
authors.initials: LC
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D003900:Desoxycorticosterone; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D012965:Sodium Chloride; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D011189:Potassium Chloride; D000077868:Atrasentan