Simvastatin prevents vascular hyporeactivity during inflammation.
BACKGROUND
There is growing evidence that statins exert anti-inflammatory and antioxidative vascular actions that are independent of lipid lowering. We tested whether hyporeactivity to the endothelium-dependent vasodilator acetylcholine (ACh) and the vasoconstrictor norepinephrine (NE) during acute experimental inflammation could be prevented by simvastatin.


RESULTS
In a randomized, placebo-controlled, parallel group study, forearm blood flow (FBF) responses to NE, ACh, and the endothelium-independent vasodilator nitroglycerin (NTG) were assessed at baseline, after 4 days of simvastatin 80 mg PO or placebo treatment, and during Escherichia coli endotoxin (lipopolysaccharide [LPS])-induced inflammation in 20 healthy volunteers. Additionally, markers of inflammation and neutrophil oxidative burst were assessed. Simvastatin and placebo had no effect on FBF or oxidative/inflammatory markers. LPS administration decreased the responses of FBF to NE by 43% (P<0.05) and decreased responses to ACh by 48% (P<0.05) but did not decrease FBF responses to NTG. Simvastatin completely preserved responses to NE and to ACh. The LPS-induced increases in neutrophil oxidative burst and plasma tumor necrosis factor-alpha concentrations were mitigated by simvastatin (P<0.05 versus placebo).


CONCLUSIONS
This study demonstrates potent vasoprotective properties of high-dose simvastatin during endotoxemia that may be useful for patients with acute systemic inflammation and associated vascular hyporeactivity.
Pleiner
Johannes
J
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Schaller
Georg
G
Mittermayer
Friedrich
F
Zorn
Stefan
S
Marsik
Claudia
C
Polterauer
Stefan
S
Kapiotis
Stylianos
S
Wolzt
Michael
M
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D004311:Double-Blind Method; D019446:Endotoxemia / Q000503:physiopathology*; D004731:Endotoxins / Q000633:toxicity; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007249:Inflammation; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D005996:Nitroglycerin / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D018384:Oxidative Stress; D016897:Respiratory Burst; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine; C044101:endotoxin, Escherichia coli; D019821:Simvastatin; D005996:Nitroglycerin; D000109:Acetylcholine; D009638:Norepinephrine