Increased bioavailability of nitric oxide after lipid-lowering therapy in hypercholesterolemic patients: a randomized, placebo-controlled, double-blind study.
BACKGROUND
Impaired endothelium-dependent vasodilation is an early sign of atherosclerosis in hypercholesterolemic patients. We hypothesized that lipid-lowering therapy can improve endothelial function and that this effect is mainly mediated by increased bioavailability of nitric oxide (NO).


RESULTS
In a randomized, double-blind, placebo-controlled trial, we studied 29 patients (age, 50+/-12 years) with hypercholesterolemia (LDL cholesterol > or = 160 mg/dL) randomly assigned to receive either fluvastatin (40 mg twice daily; 17 patients) or placebo (12 patients). Forearm blood flow was measured by plethysmography before and after 24 weeks of treatment. Endothelium-dependent vasodilation was assessed by intra-arterial infusion of acetylcholine (ACh; 3, 12, 24, and 48 microg/min) and basal NO synthesis rate by intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA; 1, 2, and 4 micromol/min). Simultaneous intra-arterial infusion of L-NMMA (4 micromol/min) and ACh (12, 24, and 48 microg/min) was used to test whether any increase in endothelium-dependent vasodilation after lipid-lowering therapy could be blocked by this NO synthase inhibitor. Endothelium-dependent vasodilation improved significantly after 24 weeks of lipid-lowering therapy compared with before therapy (ACh 24 microg/min: 240+/-34% before versus 347+/-50% after therapy; P< or =0.01) and placebo (changes between after and before therapy with ACh 24 microg/min: 108+/-39% for fluvastatin versus -26+/-32% for placebo; P< or =0.05). This improvement in endothelium-dependent vasodilation could be blocked by simultaneous administration of L-NMMA (ACh 24 microg/min plus L-NMMA 4 micromol/min: 170+/-69% before versus 219+/-47% after treatment; P=NS).


CONCLUSIONS
Lipid-lowering therapy with fluvastatin can improve disturbed endothelial function in hypercholesterolemic patients compared with placebo. This improvement is mediated by increased bioavailability of NO.
Department of Medicine IV, University of Erlangen-Nürnberg, Klinikum Nürnberg-Süd, Germany.
S
S
John
M
M
Schlaich
M
M
Langenfeld
H
H
Weihprecht
G
G
Schmitz
G
G
Weidinger
R E
RE
Schmieder
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D001682:Biological Availability; D004311:Double-Blind Method; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood* / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood*; D009599:Nitroprusside / Q000494:pharmacology; D010919:Placebos; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D008055:Lipids; D010919:Placebos; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000109:Acetylcholine