Improvement of endothelium-dependent vasodilation
Background. Statins stimulate the expression of endothelial NO synthase (eNOS) in vitro and enhance endothelium-dependent, NO-mediated vasodilation in vivo. Asymmetrical dimethylarginine (ADMA) is an endogenous, competitive inhibitor of eNOS. The presence of elevated plasma ADMA levels is associated with endothelial dysfunction. We investigated the hypothesis that simvastatin may enhance endothelial function in patients with elevated ADMA only if the inhibitory effect of ADMA is overcome by supplemental L-arginine. Methods. 15 clinically asymptomatic, elderly subjects with elevated ADMA levels received, in a randomised order, simvastatin (40 mg/day), L-arginine sustained-release (3 g/day), or a combination of both, each 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 using computer-assisted image analysis; ADMA and L-arginine plasma concentrations were determined by a validated HPLC method. Results. Analysis of 12 subjects who completed the study revealed that 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 (8.7±0.7 vs. 4.9±0.8%; p<0.02). When given in combination with L-arginine, simvastatin had a significant beneficial effect on endothelial function (9.8±1.5 vs. 5.3±0.8%; p<0.01). Endothelium-independent vasodilation by glyceryl trinitrate was not affected by any of the treatments.Larginine, either alone or in combination with simvastatin, significantly improved plasma Larginine/ADMA ratio (baseline, 82.3±4.0 vs. 102.8±9.2 and 102.6±10.8, respectively, each p<0.05). Conclusions. Simvastatin does not enhance endothelial function in subjects in whom eNOS is blocked by elevated ADMA levels; combination of simvastatin with oral L-arginine has a synergistic effect on endothelial function. 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.