NDT Advance Access originally published online on September 22, 2006
Nephrology Dialysis Transplantation 2006 21(12):3443-3449; doi:10.1093/ndt/gfl443
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Low albumin levels increase endothelial NO production and decrease vascular NO sensitivity
1Laboratory of Vascular Medicine, 2Department of Nephrology and Hypertension, University Medical Centre Utrecht, Institute and Graduate School of Biomembranes, 3Faculty of Science, Section Interface Physics, Utrecht University, Utrecht, The Netherlands and 4Division of Nephrology and Hypertension, Departments Medicine, Physiology and Biophysics, University of California, Irvine, USA
Correspondence and offprint requests to: Jaap A. Joles, DVM, PhD, Department of Nephrology and Hypertension F03.223, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Email: J.A.Joles{at}med.uu.nl
Background. Hypoalbuminaemia is associated with increased risk of cardiovascular disease. It is unclear whether endothelial dysfunction is a direct result of low albumin or whether it is caused by factors like chronic inflammation or dyslipidaemia. In this study, the effect of low albumin concentrations on endothelial nitric oxide synthase (eNOS)-dependent NO production was determined in vitro and ex vivo.
Methods. eNOS activity, assessed by arginine–citrulline conversion, and NO production, determined by 4,5-diaminofluorescein diacetate, electron paramagnetic resonance and Griess colorimetry, were measured in cultured endothelial cells expressing high levels of eNOS (bEnd.3) after exposure to albumin concentrations ranging from 0.5 mmol/l (33 g/l) to 0 mmol/l. Analbuminaemic and control rat plasma NO metabolites and aortic eNOS protein mass were determined, and aortic endothelium-independent and endothelium-dependent vasodilator tone were measured ex vivo under albumin-free conditions.
Results. In vitro, eNOS activity was significantly increased in the absence of albumin (75 ± 2 vs 26 ± 6 pmol/min/mg protein; P < 0.01). Low albumin levels consistently increased NO production in endothelial cells. Plasma NO metabolites were increased (18.2 ± 1.9 vs 12.5 ± 0.8 µmol/l; P < 0.05) and endothelium-independent relaxation was markedly blunted in analbuminaemic rats, resulting in a considerably higher ED50 (80 ± 2 vs 1.1 ± 0.2 nmol/l, P < 0.01), while endothelium-dependent dilatation was slightly, but significantly, increased. Aortic eNOS protein mass was not affected. This implies that in vivo hypoalbuminaemia reduces vascular NO sensitivity.
Conclusion. We show that low albumin as such seems to enhance, rather than diminish, eNOS-mediated endothelial NO production.
Keywords: analbuminaemia; endothelial nitric oxide synthase; NO
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