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CLINICAL STUDY

Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks

^a Department of Medicine IV, University of Erlangen-Nürnberg, Klinikum Nürnberg-Süd, Nürnberg, Germany
^b Department of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany

Manuscript received July 25, 2000; revised manuscript received November 22, 2000, accepted December 21, 2000.

Reprint requests and correspondence: Prof. Dr. Roland E. Schmieder, Department of Medicine IV/4, University of Erlangen-Nürnberg, Klinikum Nürnberg-Süd, Breslauerstr. 201, D-90471 Nürnberg, Germany
Roland.Schmieder{at}rzmail.uni-erlangen.de

OBJECTIVES

We investigated whether improvement of endothelial dysfunction in hypercholesterolemia can be achieved with short-term lipid-lowering therapy.

BACKGROUND

Impaired endothelium-dependent vasodilation plays a pivotal role in the pathogenesis of atherosclerosis and acute coronary syndromes.

METHODS

In a randomized, double-blind, placebo-controlled trial, we studied 37 patients (52 ± 11 yrs) with low density lipoprotein cholesterol 160 mg/dl (196 ± 44 mg/dl) randomly assigned to either cerivastatin (0.4 mg/d) or placebo. Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh 12, 48 µg/min) and endothelium-independent vasodilation by intra-arterial infusion of nitroprusside (3.2, 12.8 µg/min).

RESULTS

Low density lipoprotein cholesterol decreased after two weeks of treatment (cerivastatin –33 ± 4% vs. placebo + 2 ± 4%, x ± SEM, p < 0.001). Endothelium-dependent vasodilation improved after two weeks of therapy with cerivastatin compared with baseline (ACh 12 µg/min: + 22.3 ± 5.2 vs. + 11.2 ± 1.9 ml/min/100 ml, p < 0.01; ACh 48 µg/min: +31.2 ± 6.3 vs. +19.1 ± 3.1 ml/min/100 ml, p < 0.05). In contrast, changes in forearm blood flow to ACh were similar before and after therapy in the placebo group (ACh 12 µg/min: +12.9 ± 3.6 vs. +9.0 ± 1.9 ml/min/100 ml, NS; ACh 48 µg/min: +20.7 ± 3.7 vs. 19.4 ± 2.9 ml/min/100 ml, NS). Endothelium-dependent vasodilation improved in comparison with placebo (ACh 48 µg/min: +203 ± 85% [cerivastatin] vs. –26 ± 71% [placebo], p < 0.05). This improvement in endothelium-dependent vasodilation was no longer observed when the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine was coinfused (ACh 48 µg/min + N(G)-monomethyl-L-arginine 4 µmol/min –48 ± 85% [cerivastatin]).

CONCLUSIONS

Short-term lipid-lowering therapy with cerivastatin can improve endothelial function and NO bioavailability after two weeks in patients with hypercholesterolemia.

Abbreviations and Acronyms   ACh = acetylcholine   ANOVA = analysis of variance   FBF = forearm blood flow   HDL = high density lipoprotein   LDL = low density lipoprotein   L-NMMA = N(G)-monomethyl-L-arginine   NO = nitric oxide   PAI-1 = plasminogen activator inhibitor type 1   t-PA = tissue-type plasminogen activator

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