Authors
Boger RH. Bode-Boger SM. Brandes RP. Phivthong-ngam L. Bohme M. Nafe R.
Mugge A. Frolich JC.
Institution
Institute of Clinical Pharmacology, Medical School, Hannover, Germany.
Title
Dietary L-arginine reduces
the progression of
atherosclerosis in cholesterol-fed rabbits: comparison with
lovastatin.
Source
Circulation. 96(4):1282-90, 1997 Aug 19.
Abstract
BACKGROUND: We investigated whether
L-arginine induces regression of preexisting
atheromatous lesions and reversal of
endothelial dysfunction in hypercholesterolemic rabbits,
whether similar effects can be obtained by
cholesterol-lowering therapy with lovastatin, and which
mechanism leads to these effects. METHODS AND RESULTS:
Rabbits were fed 1% cholesterol for 4 weeks and 0.5% cholesterol for an
additional 12 weeks. Two groups of cholesterol-fed rabbits were treated with
L-arginine (2.0% in drinking water) or lovastatin (10 mg/d)
during weeks 5 through 16. Systemic nitric oxide (NO) formation was assessed
as the urinary excretion rates of nitrate and cGMP in weekly
intervals. Cholesterol feeding progressively reduced urinary nitrate
excretion to approximately 40% of baseline (P<.05) and increased plasma
concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO
synthesis inhibitor. Dietary
L-arginine reversed the reduction in plasma
L-arginine/ADMA ratio and partly restored urinary excretion
of nitrate and cGMP (each P<.05 vs cholesterol) but did not change plasma
cholesterol levels. L-Arginine completely blocked
the progression of carotid intimal plaques,
reduced aortic intimal thickening, and preserved
endothelium-dependent vasodilator function. Lovastatin
treatment reduced plasma cholesterol by 32% but did not improve urinary
nitrate or cGMP excretion or endothelium-dependent
vasodilation. Lovastatin had a weaker inhibitory effect on carotid plaque
formation and aortic intimal thickening than L-arginine.
L-Arginine inhibited but lovastatin potentiated superoxide
radical generation in the atherosclerotic
vascular wall. CONCLUSIONS: Dietary
L-arginine improves NO-dependent vasodilator function in
cholesterol-fed rabbits and completely blocks the
progression of plaques via restoration of NO synthase
substrate availability and reduction of vascular oxidative stress. Lovastatin
treatment has a weaker inhibitory effect on the
progression of atherosclerosis and no
effect on vascular NO elaboration, which may be due to its stimulatory effect
on vascular superoxide radical generation.