Journal Article

CyA and OxLDL cause endothelial dysfunction in isolated arteries through endothelin-mediated stimulation of O<sub>2</sub><sup>−</sup> formation

Jan Galle, Cordula Lehmann-Bodem, Ullrich Hübner, Alexandra Heinloth and Christoph Wanner

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 15, issue 3, pages 339-346
Published in print March 2000 | ISSN: 0931-0509
Published online March 2000 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/15.3.339
CyA and OxLDL cause endothelial dysfunction in isolated arteries through endothelin-mediated stimulation of O2− formation

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Background. Cyclosporin A (CyA) and oxidized low-density lipoprotein (OxLDL) cause endothelial dysfunction, partly through stimulation of O2 formation (which can inactivate nitric oxide). We investigated whether CyA and OxLDL potentiate their influence on oxidative stress, whether endothelin (ET) is a mediator of CyA- and OxLDL-induced O2 formation, and whether enhanced oxidative stress results in further attenuation of endothelium-dependent vasodilation.

Methods and results. Human LDL was oxidized by Cu++. O2 formation of isolated rat aortic rings was measured using a chemiluminescence assay. Incubation (60 min) of aortic rings with CyA (10 ng–10 μg/ml) or with OxLDL (300 μg/ml) caused a significant, dose-dependent increase of the basal O2 formation. Pretreatment of the aortic rings with CyA (10 ng/ml) further enhanced the OxLDL-induced O2 formation by factor 1.9. The enhancement of the OxLDL-induced stimulation of O2 formation by CyA could be completely blocked by BQ123, a selective endothelin-1 (ET-1) receptor antagonist. Likewise, exogenously applied ET-1 (1 nM) potentiated the OxLDL-induced O2 formation by factor 1.8. Endothelium-dependent dilation was measured in isolated rings of rabbit aorta superfused with physiological salt solution in an organ bath. Incubation of the aortic rings with CyA (10 μg/ml, 60 min) or with OxLDL (300 μg/ml, 60 min) alone did not attenuate endothelium-dependent dilations. However, coincubation of the aortic rings with CyA+OxLDL in the presence of diethyl-dithio-carbamate, an inhibitor of the endogenous superoxide dismutase, caused a 60% inhibition of acetylcholine-induced dilator responses.

Conclusions. Coincubation of isolated aortic rings with CyA and OxLDL causes a potent enhancement of vascular O2 formation. ET-1 seems to be mediator of the CyA-induced O2 formation. Enhanced oxidative stress results in further attenuation of endothelium dependent vasodilation.

Keywords: atherosclerosis; endothelin; endothelium; oxidative stress; superoxide radical; transplantation

Journal Article.  5846 words.  Illustrated.

Subjects: Nephrology

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