(Circulation. 1997;96:1282-1290.)
© 1997 American Heart Association, Inc.
Articles |
Dietary L-Arginine Reduces the Progression of Atherosclerosis in Cholesterol-Fed Rabbits
Comparison With Lovastatin
From the Institute of Clinical Pharmacology (R.H.B., S.M.B.-B., L.P., M.B., J.C.F.) and Departments of Cardiology (R.P.B., A.M.) and Pathology (R.N.), Medical School, Hannover, Germany.
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 
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.
Key Words: endothelium-derived factors • endothelium • free radicals • lipoproteins • plaque
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