Nephrol Dial Transplant (2000) 15: 339-346
© 2000 European Renal Association-European Dialysis and Transplant Association
CyA and OxLDL cause endothelial dysfunction in isolated arteries through endothelin-mediated stimulation of O2- formation
Department of Medicine, Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany
Correspondence and offprint requests to: Dr Jan Galle, Department of Medicine, Division of Nephrology, University Hospital Würzburg, Joseph-Schneider-Str. 2, D-97080 Würzburg, Germany.
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
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