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

Abstract

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.