title: Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice.
abstract: 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 ETA 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 ETA 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 micromol/liter, P < 0.01). Treatment with the ETA 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 micromol/liter, P < 0.05). Chronic ETA 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 ETA 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. ETA receptor blockade may have therapeutic potential in patients with atherosclerosis.
authors.affiliation: Cardiology, University Hospital Zürich and Cardiovascular Research Laboratory, Institute of Physiology, University of Zürich, CH-8091 Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Barton
authors.forename: C C
authors.initials: CC
authors.lastname: Haudenschild
authors.forename: L V
authors.initials: LV
authors.lastname: d'Uscio
authors.forename: S
authors.initials: S
authors.lastname: Shaw
authors.forename: K
authors.initials: K
authors.lastname: Münter
authors.forename: T F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004032:Diet; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D009569:Nitric Oxide / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D013045:Species Specificity; D013599:Systole; D014280:Triglycerides / Q000097:blood; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D008074:Lipoproteins; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D014280:Triglycerides; D009599:Nitroprusside; D009569:Nitric Oxide; C107831:darusentan; D002784:Cholesterol; D000109:Acetylcholine; D009638:Norepinephrine