Abstract 863: Improvement of Endothelial Function by Simvastatin Depends on the Plasma Level of Asymmetric Dimethylarginine
The endothelial NO synthase (eNOS), key enzyme in the biosynthesis of NO in endothelial cells, is upregulated by statins leading to an enhanced endothelial function. In some studies statins failed to improve endothelial function. We hypothesised that the level of asymmetric dimethylarginine (ADMA) - an endogenous inhibitor of eNOS - might be the explanation for this phenomenon. 15 healthy subjects with elevated plasma ADMA levels and 13 healthy subjects with low plasma ADMA levels received in a randomized order, simvastatin (40 mg/day), L-arginine sustained release (3 g/day), or a combination of both, each treatment for 3 weeks, in a three period crossover design with at least three weeks of wash-out between treatments. Endothelium-dependent vasodilation was assessed by brachial artery ultrasound; ADMA and L-arginine concentrations were determined by a validated HPLC method. In subjects with elevated plasma ADMA levels simvastatin had no effect on endothelium-dependent vasodilation when administered alone (6.2±1.2% vs. 6.1±0.9%). L-arginine significantly improved endothelial function when given alone (8.7±0.7% vs. 4.9±0.8%; p<0.02) or in combination with simvastatin (9.8±1.5% vs. 5.3±0.8%; p<0.01). Endothelium-independent vasodilation was not affected. In subjects with low plasma ADMA levels administration of simvastatin, L-arginine as well as their combination all led to a significant increase in endothelium-dependent vasodilation (simvastatin: 9.47±3.16% vs. 6.08±3.77% at baseline; p < 0.001; L-arginine: 10.16±2.85% vs. 5.69±2.99% at baseline; p = 0.02; simvastatin + L-arginine: 8.99±3.06% vs. 6.34±3.26% at baseline; p = 0.001). Endothelium-independent vasodilation was not significantly affected by any of the treatments. In subjects with low ADMA levels all three treatments improved endothelial function whereas simvastatin did not enhance endothelial function in subjects in whom eNOS activity was reduced by elevated ADMA levels. Only in combination with oral L-arginine simvastatin did improve endothelial function in these subjects. As NO-mediated effects may play a major role in therapeutic effects of statins, combination with L-arginine should be considered in patients with elevated ADMA concentration.