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.
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.


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 x kg(-1) x 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.
Behr-Roussel
D
D
Department of Cardiovascular Surgery, Hôpital Broussais, Paris, France.
Rupin
A
A
Simonet
S
S
Bonhomme
E
E
Coumailleau
S
S
Cordi
A
A
Serkiz
B
B
Fabiani
J N
JN
Verbeuren
T J
TJ
D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001120:Arginine / Q000097:blood / Q000627:therapeutic use*; D001772:Blood Cell Count; D002791:Cholesterol, Dietary; D003094:Collagen / Q000032:analysis; D003324:Coronary Artery Disease / Q000150:complications* / Q000517:prevention & control; D003331:Coronary Vessels / Q000201:enzymology / Q000473:pathology; D006152:Cyclic GMP / Q000032:analysis; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006439:Hemodynamics; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000209:etiology; D007150:Immunohistochemistry; D008239:Lysine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D008264:Macrophages / Q000276:immunology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D011817:Rabbits; D013601:T-Lymphocytes / Q000276:immunology
D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D003094:Collagen; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D006152:Cyclic GMP; D008239:Lysine