Asymmetric dimethylarginine determines the improvement of endothelium-dependent vasodilation by simvastatin: Effect of combination with oral L-arginine.
OBJECTIVE
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.
Böger
Gerhild I
GI
Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology, Hamburg, Germany.
Rudolph
Tanja K
TK
Maas
Renke
R
Schwedhelm
Edzard
E
Dumbadze
Ekaterina
E
Bierend
Anneke
A
Benndorf
Ralf A
RA
Böger
Rainer H
RH
D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000378:metabolism; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D019821:Simvastatin / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D002097:C-Reactive Protein; D001120:Arginine; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III