HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: j.jacc.2007.02.051v1 49/23/2274    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Böger, G. I. Articles by Böger, R. H. Search for Related Content PubMed Articles by Böger, G. I. Articles by Böger, R. H.

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, Hamburg, Germany
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

This article has been cited by other articles:

				G. M. J. M. Welten, M. Chonchol, O. Schouten, S. Hoeks, J. J. Bax, R. T. van Domburg, M. van Sambeek, and D. Poldermans Statin use is associated with early recovery of kidney injury after vascular surgery and improved long-term outcome Nephrol. Dial. Transplant., July 15, 2008; (2008) gfn381v1. [Abstract] [Full Text] [PDF]

				M. C. Cave, R. T. Hurt, T. H. Frazier, P. J. Matheson, R. N. Garrison, C. J. McClain, and S. A. McClave Obesity, Inflammation, and the Potential Application of Pharmaconutrition Nutr Clin Pract, February 1, 2008; 23(1): 16 - 34. [Abstract] [Full Text] [PDF]

				R. Maas, E. Schwedhelm, L. Kahl, H. Li, R. Benndorf, N. Luneburg, U. Forstermann, and R. H. Boger Simultaneous Assessment of Endothelial Function, Nitric Oxide Synthase Activity, Nitric Oxide-Mediated Signaling, and Oxidative Stress in Individuals with and without Hypercholesterolemia Clin. Chem., February 1, 2008; 54(2): 292 - 300. [Abstract] [Full Text] [PDF]

				R. Schnabel and S. Blankenberg Oxidative Stress in Cardiovascular Disease: Successful Translation From Bench to Bedside? Circulation, September 18, 2007; 116(12): 1338 - 1340. [Full Text] [PDF]