Objective: This study investigated whether endothelial dysfunction occurs in mesenteric arteries of apoE-deficient mice and determined the role of endothelin (ET)-1, which is increased in human atherosclerosis, using an orally active endothelin ET receptor antagonist. A Methods: ApoE-deficient and C57BL / 6J control mice were fed for 30 weeks with normal chow or high-fat Western-type diet alone or in combination with darusentan (LU135252; 50 mg / kg / day). Vasomotor reactivity of isolated

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... mesenteric arteries (I.D. 200-250 mm) was studied in vitro under perfused and pressurized conditions. Results: In both mouse strains, about one fourth of the endotheliumdependent relaxant response to acetylcholine was insensitive to inhibition by L-NAME and indomethacin. In mesenteric arteries of apoE-deficient mice on Western-type diet, increased intima-media thickness and levels of endothelin-1 protein were observed. In addition, NO-mediated endothelium-dependent relaxation to acetylcholine was reduced without affecting L-NAME / indomethacin insensitive relaxation and contractions to endothelin-1 and serotonin were enhanced. Treatment with darusentan normalized vascular structure, NO-mediated relaxation to acetylcholine and contractions to endothelin-1 and serotonin without affecting blood pressure or plasma cholesterol levels. Conclusions: Severe hypercholesterolemia in apoE-deficient mice is associated with attenuation of NO-mediated relaxation to acetylcholine and increased vascular endothelin-1 content. Chronic ET receptor blockade may provide a new therapeutic A approach to improve NO-mediated endothelium-dependent vasomotion in small arteries.