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CLINICAL RESEARCH: ENDOTHELIAL FUNCTION

Asymmetric Dimethylarginine Determines the Improvement of Endothelium-Dependent Vasodilation by Simvastatin

Effect of Combination With Oral L-Arginine

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^_*,_*

^_* Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology
Department of Cardiology, University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Manuscript received June 16, 2006; revised manuscript received February 7, 2007, accepted February 13, 2007.

^_* Reprint requests and correspondence: Dr. Rainer H. Böger, Institut für Experimentelle und Klinische Pharmakologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. (Email: boeger{at}uke.uni-hamburg.de).

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.

Abbreviations and Acronyms   ADMA = asymmetric dimethylarginine   eNOS = endothelial nitric oxide synthase   FMD = flow-mediated dilation   HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A   LDL = low-density lipoprotein   NO = nitric oxide   SR = sustained release

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