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Chronic ETA receptor blockade prevents endothelial dysfunction of small arteries in apolipoprotein E-deficient mice

d'Uscio, Livius V. ; Barton, Matthias ; Shaw, Sidney ; Lüscher, Thomas F.

In: Cardiovascular Research, 2002, vol. 53, no. 2, p. 487-495

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    Title
    • Chronic ETA receptor blockade prevents endothelial dysfunction of small arteries in apolipoprotein E-deficient mice
    Author
    • d'Uscio, Livius V.. Cardiovascular Research, Institute of Physiology, University of Zürich and Cardiology and University Hospital, Zürich, Switzerland
    • Barton, Matthias. Clinical Atherosclerosis and Genetic Research Laboratory, University Hospital Zurich, Zurich, Switzerland
    • Shaw, Sidney. Department of Clinical Research, University Hospital, Bern, Switzerland
    • Lüscher, Thomas F.. Cardiovascular Research, Institute of Physiology, University of Zürich and Cardiology and University Hospital, Zürich, Switzerland
    Document Type
    • Postprint
    OAI-PMH Identifier
    • oai:doc.rero.ch:303649
    Summary
    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 ETA receptor antagonist. 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 small mesenteric arteries (I.D. 200-250 μm) was studied in vitro under perfused and pressurized conditions. Results: In both mouse strains, about one fourth of the endothelium-dependent 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 ETA receptor blockade may provide a new therapeutic approach to improve NO-mediated endothelium-dependent vasomotion in small arteries