Author + information
- Received June 16, 2006
- Revision received February 7, 2007
- Accepted February 13, 2007
- Published online June 12, 2007.
- Gerhild I. Böger, PhD⁎,
- Tanja K. Rudolph, MD⁎,†,
- Renke Maas, MD⁎,
- Edzard Schwedhelm, PhD⁎,
- Ekaterina Dumbadze⁎,
- Anneke Bierend⁎,
- Ralf A. Benndorf, MD⁎ and
- Rainer H. Böger, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Rainer H. Böger, Institut für Experimentelle und Klinische Pharmakologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
Objectives We hypothesized that the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide (NO) synthase (eNOS), might determine the endothelial effects of statins.
Background Endothelial NO synthase is up-regulated by statins. However, statins failed to improve endothelial function in some studies. Asymmetric dimethylarginine inhibits eNOS by a mechanism that is reversible by L-arginine.
Methods Ninety-eight clinically asymptomatic elderly subjects had their plasma ADMA levels screened. Those in the highest (high ADMA, n = 15) and lowest quartiles of the ADMA distribution (low ADMA, n = 13) were eligible to receive, in a randomized order, simvastatin (40 mg/day), L-arginine (3 g/day), or a combination of both, each for 3 weeks. Endothelium-dependent vasodilation (EDD) was assessed by brachial artery ultrasound.
Results Simvastatin had no effect on EDD in subjects with high ADMA (6.2 ± 1.2% vs. 6.1 ± 0.9%), whereas simvastatin plus L-arginine significantly improved EDD (9.8 ± 1.5% vs. 5.3 ± 0.8%; p < 0.01). In subjects with low ADMA, simvastatin improved endothelial function when given alone (9.5 ± 3.2% vs. 6.1 ± 3.8%; p < 0.001) or in combination with L-arginine (9.0 ± 3.1% vs. 6.3 ± 3.3%; p = 0.001). L-arginine alone improved endothelial function in both groups. Endothelium-independent vasodilation was not affected.
Conclusions Simvastatin does not enhance endothelial function in subjects with elevated ADMA, whereas it does so in patients with low ADMA. Combination of simvastatin with oral L-arginine improves endothelial function in subjects with high ADMA, but has no additional effect in subjects with low ADMA. As NO-mediated effects may play a major role in the therapeutic effects of statins, ADMA concentration is an important factor that influences the “pleiotropic” effects of simvastatin.
This study was supported, in part, by eNOS Pharmaceuticals, Inc., Cambridge, Massachusetts. Drs. Böger, Maas, Schwedhelm, and Benndorf have a share in patents on asymmetric dimethylarginine assays and receive royalties from the licenses. Drs. Böger and Rudolph contributed equally to this work.
- Received June 16, 2006.
- Revision received February 7, 2007.
- Accepted February 13, 2007.
- American College of Cardiology Foundation