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.
John
S
S
Department of Medicine IV, University of Erlangen-Nürnberg, Klinikum Nürnberg-Süd, Germany.
Schlaich
M
M
Langenfeld
M
M
Weihprecht
H
H
Schmitz
G
G
Weidinger
G
G
Schmieder
R E
RE
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