Proceedings of the National Academy of Sciences - PNAS, 1998-11-24, Vol.95 (24), p.14367-14372
This study investigated whether endothelin-1 (ET-1), a potent vasoconstrictor, which also stimulates cell proliferation, contributes to endothelial dysfunction and atherosclerosis. Apolipoprotein E (apoE)-deficient mice and C57BL/6 control mice were treated with a Western-type diet to accelerate atherosclerosis with or without ET A receptor antagonist LU135252 (50 mg/kg/d) for 30 wk. Systolic blood pressure, plasma lipid profile, and plasma nitrate levels were determined. In the aorta, NO-mediated endothelium-dependent relaxation, atheroma formation, ET receptor-binding capacity, and vascular ET-1 protein content were assessed. In apoE-deficient but not C57BL/6 mice, severe atherosclerosis developed within 30 wk. Aortic ET-1 protein content ( P 〈 0.0001) and binding capacity for ET A receptors was increased as compared with C57BL/6 mice. In contrast, NO-mediated, endothelium-dependent relaxation to acetylcholine (56 ± 3 vs. 99 ± 2%, P 〈 0.0001) and plasma nitrate were reduced (57.9 ± 4 vs. 93 ± 10 μmol/liter, P 〈 0.01). Treatment with the ET A receptor antagonist LU135252 for 30 wk had no effect on the lipid profile or systolic blood pressure in apoE-deficient mice, but increased NO-mediated endothelium-dependent relaxation (from 56 ± 3 to 93 ± 2%, P 〈 0.0001 vs. untreated) as well as circulating nitrate levels (from 57.9 ± 4 to 80 ± 8.3 μmol/liter, P 〈 0.05). Chronic ET A receptor blockade reduced elevated tissue ET-1 levels comparable with those found in C57BL/6 mice and inhibited atherosclerosis in the aorta by 31% without affecting plaque morphology or ET receptor-binding capacity. Thus, chronic ET A receptor blockade normalizes NO-mediated endothelial dysfunction and reduces atheroma formation independent of plasma cholesterol and blood pressure in a mouse model of human atherosclerosis. ET A receptor blockade may have therapeutic potential in patients with atherosclerosis.
Acetylcholine - pharmacology ; Animals ; Aorta, Thoracic - drug effects ; Aorta, Thoracic - pathology ; Aorta, Thoracic - physiopathology ; Apolipoproteins E - deficiency ; Arteriosclerosis - pathology ; Arteriosclerosis - physiopathology ; Arteriosclerosis - prevention & control ; Biological Sciences ; Blood Pressure - drug effects ; Cardiovascular disease ; Cholesterol - blood ; Diet ; Endothelin Receptor Antagonists ; Endothelin-1 - blood ; Endothelin-1 - pharmacology ; Endothelin-1 - physiology ; Endothelium, Vascular - drug effects ; Endothelium, Vascular - physiology ; Endothelium, Vascular - physiopathology ; Humans ; In Vitro Techniques ; Lipoproteins - blood ; Male ; Medical research ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Muscle, Smooth, Vascular - drug effects ; Muscle, Smooth, Vascular - pathology ; Muscle, Smooth, Vascular - physiopathology ; Nitric Oxide - physiology ; Nitroprusside - pharmacology ; Norepinephrine - pharmacology ; Phenylpropionates - pharmacology ; Pyrimidines - pharmacology ; Receptor, Endothelin A ; Rodents ; Species Specificity ; Systole ; Triglycerides - blood ; Vasodilation - drug effects
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