© 2002 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Chronic ETA receptor blockade prevents endothelial dysfunction of small arteries in apolipoprotein E-deficient mice
aCardiovascular Research, Institute of Physiology, University of Zürich and Cardiology and University Hospital, Zürich, Switzerland
bDepartment of Clinical Research, University Hospital, Bern, Switzerland
cClinical Atherosclerosis and Genetic Research Laboratory, University Hospital Zurich, Zurich, Switzerland
* Corresponding author. University Hospital Zürich, Rämistrasse 100 CH-8091, Zürich, Switzerland. Tel.: +41-1-255-2121/2177; fax: +41-1-255-4251 cardiotfl{at}gmx.ch
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.
KEYWORDS Endothelins; Endothelial receptors; Endothelial function; Lipoproteins; Nitric oxide
1 The first two authors contributed equally to this work.
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