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). Methods and Results - In a randomized, double-blind, placebo-controlled trial, we studied 29 patients (age, 50 ± 12 years) with hypercholesterolemia (LDL cholesterol ≤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 μg/min) and basal NO synthesis rate by intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA; 1, 2, and 4 μmol/min). Simultaneous intra-arterial infusion of L-NMMA (4 μmol/min) and ACh (12, 24, and 48 μg/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 μg/min: 240±34% before versus 347±50% after therapy; P≤0.01) and placebo (changes between after and before therapy with ACh 24 μg/min: 108±39% for fluvastatin versus -26±32% for placebo; P≤0.05). This improvement in endothelium-dependent vasodilation could be blocked by simultaneous administration of L-NMMA (ACh 24 μg/min plus L-NMMA 4 μmol/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.