(Circulation. 2000;102:1033.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Effect of Chronic Treatment With the Inducible Nitric Oxide Synthase Inhibitor N-Iminoethyl-L-Lysine or With L-Arginine on Progression of Coronary and Aortic Atherosclerosis in Hypercholesterolemic Rabbits
From the Department of Cardiovascular Surgery, Hôpital Broussais, Paris (D.B.-R., J.-N.F.), and the Division of Angiology, Servier Research Institute, Suresnes (A.R., S.S., E.B., S.C., A.C., B.S., T.J.V.), France.
Correspondence to Tony J. Verbeuren, PhD, Division of Angiology, Servier Research Institute, 11 Rue des Moulineaux, 92150 Suresnes, France. E-mail tover{at}netgrs.com
Background—We examined the implications of iNOS in atherosclerosis progression using the selective inducible NO synthase (iNOS) inhibitor N-iminoethyl-L-lysine (L-NIL) in hypercholesterolemic rabbits.
Methods and Results—Nine rabbits were fed a 0.3% cholesterol diet for 24 weeks (Baseline group); 25 animals were maintained on the diet and treated for 12 extra weeks with L-NIL (5 mg · kg-1 · d-1, L-NIL group, n=8), vehicle (Saline group, n=9), or L-arginine (2.25%, L-Arg group, n=8). In abdominal aortas of Saline rabbits, the lesions (53.7±5.7%, Baseline) increased to 75.0±5.0% (P<0.05) but remained unaltered in the L-NIL group (63.4±6.6%). Similar results were obtained for the intima/media ratio in thoracic aortas. In coronary arteries, the intima/media ratio was comparable in Baseline (0.68±0.18) and Saline (0.96±0.19) rabbits but decreased to 0.34±0.19 (P<0.05) in L-NIL rabbits. L-Arginine had beneficial effects only in abdominal aortas. An increased thoracic aorta collagen content was found in Saline and L-Arg but not in L-NIL rabbits. In thoracic aortas of the Saline group, acetylcholine caused modest relaxations that slightly increased by L-arginine but not by L-NIL. Relaxations to nitroglycerin were ameliorated by L-NIL.
Conclusions—This is the first study showing that chronic treatment with an iNOS inhibitor, L-NIL, limits progression of preexisting atherosclerosis in hypercholesterolemic rabbits. Increased intimal collagen accumulation may participate in iNOS-induced atherosclerosis progression.
Key Words: nitric oxide synthase • L-NIL • arginine • atherosclerosis • inhibitors
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