Lipid-independent effects of statins on endothelial function and bioavailability of nitric oxide in hypercholesterolemic patients.
BACKGROUND
Experimental evidence suggests a lipid-independent effect of statins on endothelial function and nitric oxide (NO) availability in humans. We investigated whether improvement in NO availability in hypercholesterolemia can be achieved rapidly with statins before lipid-lowering therapy is complete.


METHODS
We studied 41 patients (52 +/- 11 years) with low-density lipoprotein (LDL) cholesterol > or = 130 mg/dL (179 +/- 45 mg/dL) randomly assigned to treatment either with atorvastatin (20 mg/day) or cerivastatin (0.4 mg/day). Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh) after 3 days (n = 18) and 14 days (n = 39) of treatment. NO availability and oxidative stress were assessed by coinfusion of l-NMMA and vitamin C.


RESULTS
After 3 days of treatment, LDL-cholesterol decreased by 11.9% with a further decrease to 29.6% after 14 days ( P < .001). Endothelium-dependent vasodilation improved by +46.7% after 3 days of statin therapy compared with before therapy (ACh 48 microg/min: +15.7 +/- 10.6 vs +10.7 +/- 10.8 mL/min per 100 mL, P < .05). No further improvement in endothelium-dependent vasodilation (+42.7% compared with before therapy) could be demonstrated after 14 days of treatment (ACh 48 microg/min: +17.7 +/- 10.3 vs +12.4 +/- 9.3 mL/min per 100 mL before therapy, P < .001). Coinfusion of ACh plus vitamin C was able to improve endothelium-dependent vasodilation before but not after 3 or 14 days of statin therapy either. The improvement in endothelium-dependent vasodilation after therapy was no longer observed when the NO-synthase inhibitor l-NMMA was coinfused together with ACh.


CONCLUSIONS
Short-term lipid-lowering therapy with statins is able to improve endothelial function and NO availability almost completely after 3 days in hypercholesterolemic patients probably by decreasing oxidative stress. This improvement seems to be more rapid than the accompanying decline in LDL-cholesterol and not related to these lipid changes. This finding can support the concept of lipid-independent effects of statins in humans.
John
Stefan
S
Department of Medicine IV, University of Erlangen-Nürnberg, Erlangen, Germany. stefan.john@rzmail.uni-erlangen.de
Schneider
Markus P
MP
Delles
Christian
C
Jacobi
Johannes
J
Schmieder
Roland E
RE
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001205:Ascorbic Acid / Q000494:pharmacology; D000069059:Atorvastatin; D001682:Biological Availability; D002097:C-Reactive Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000493:pharmacokinetics*; D009599:Nitroprusside / Q000494:pharmacology; D011725:Pyridines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D012039:Regional Blood Flow / Q000187:drug effects; D014664:Vasodilation; D019323:omega-N-Methylarginine / Q000494:pharmacology
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D002097:C-Reactive Protein; D000069059:Atorvastatin; C086276:cerivastatin; D000109:Acetylcholine; D001205:Ascorbic Acid