Low albumin levels increase endothelial NO production and decrease vascular NO sensitivity.

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 micromol/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.

Hypoalbuminaemia enhances the renal vasoconstrictor effect of lysophosphatidylcholine.

BACKGROUND: Lysophosphatidylcholine (LPC) causes vascular dysfunction in vitro. Lipoprotein LPC is increased in hypoalbuminaemia. Albumin binds LPC and restores LPC-induced abnormalities. We hypothesized that in vivo LPC impairs blood flow more in hypoalbuminaemia than in normoalbuminaemia. METHODS: Increasing concentrations of LPC were infused intra-renally in Nagase analbuminaemic rats (NAR) and Sprague-Dawley rats (controls). RESULTS: Intra-renal LPC (0.1 micromol/min, 20 min) reduced renal blood flow (RBF) more (P < 0.01) in NAR (from 8.3 +/- 0.3 to 4.0 +/- 1.1) than in controls (from 7.7 +/- 0.7 to 5.8 +/- 0.5 ml/min/g kidney). Lysophosphatidylethanolamine had no effect. After stopping LPC, RBF recovery was delayed in NAR [median 90 (range: 70-90) vs 45 min (40-60), P < 0.01]. Intravenous bovine serum albumin (BSA) prevented LPC-induced vasoconstriction in both strains. Prolonging LPC for 60 min delayed recovery of RBF. In this setting, intra-renal BSA completely restored RBF in 75 min (30-90), while intra-renal saline over 75 min only resulted in 33 +/- 13% recovery (P < 0.01). Baseline renal LPC content was unchanged in NAR. However, intra-renal LPC infusion doubled renal LPC content in NAR, but had no effect in controls. CONCLUSIONS: In NAR, baseline RBF and renal LPC content are normal. However, exposure of NAR to LPC results in much more vasoconstriction and accumulation of LPC than in normoalbuminaemia. Addition of albumin prevents and restores LPC-induced vasoconstriction.