© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Coronary Endothelial Function Is Preserved With Chronic Endothelin Receptor Antagonism in Experimental Hypercholesterolemia In Vitro
From the Department of Internal Medicine, Division of Cardiovascular Diseases (P.J.M.B., D.R., D.R.H., A.L.), the Division of Hypertension (L.O.L.), and the Department of Physiology and Biophysics (J.C.R.), Mayo Clinic and Mayo Foundation, Rochester, Minn.
Correspondence to Amir Lerman, MD, Department of Internal Medicine and Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail lerman.amir{at}mayo.edu
Abstract—Hypercholesterolemia is associated with increased circulating and tissue endothelin-1 immunoreactivity, decreased nitric oxide (NO) activity, and altered endothelial function. We tested the hypothesis that chronic endothelin receptor antagonism preserves endothelial function and increases NO in experimental porcine hypercholesterolemia. Pigs were randomized to 3 groups: Group 1, a 2% high-cholesterol (HC) diet alone (n=7); group 2, RO-48-5695, a combined endothelin receptor antagonist, and an HC diet (n=8); and group 3, ABT-627, a selective endothelin-A receptor antagonist, and an HC diet (n=8). Coronary epicardial and arteriolar endothelial function was determined by a dose-response relaxation to bradykinin (10-11 to 10-6 mol/L), in all groups and in pigs maintained on a normal diet. Plasma total oxidized products of NO (NOx) were determined by chemiluminescence at baseline and after 12 weeks. Bradykinin-stimulated coronary epicardial and arteriolar relaxation in group 1 was attenuated compared with normal-diet controls. This relaxation was normalized with endothelin receptor antagonism. Plasma NOx decreased after 12 weeks in group 1 (-74.8±5.5%). This decrease was attenuated in the endothelin receptor antagonist groups (group 2, -28.2±15.0%; group 3, -38.9±20.6%). Chronic endothelin receptor antagonism preserves coronary endothelial function and increases NO in hypercholesterolemia. This study supports a role of endothelin-1 in the regulation of NO activity and suggests a possible therapeutic role for endothelin receptor antagonists in hypercholesterolemia.
Key Words: coronary vessels • hypercholesterolemia • endothelin receptors • nitric oxide • oxidative stress
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