title: Long-term treatment with N(omega)-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice.
abstract: BACKGROUND
  N(omega)-nitro-L-arginine methyl ester (l-NAME) is widely used to inhibit endothelial synthesis of NO in vivo. However, it is controversial whether the long-term vascular effects of l-NAME are mediated primarily by inhibition of endothelial NO synthesis. We addressed this point in mice that are deficient in the endothelial NO synthase gene (eNOS-KO mice).
  
  
  RESULTS
  Wild-type and eNOS-KO mice received l-NAME in drinking water for 8 weeks. In wild-type mice, long-term treatment with l-NAME caused significant medial thickening and perivascular fibrosis in coronary microvessels but not in large coronary arteries. Importantly, in eNOS-KO mice, treatment with l-NAME also caused an extent of medial thickening and perivascular fibrosis in coronary microvessels that was comparable to that in wild-type mice and that was not prevented by supplementation of L-arginine. Vascular NO and cGMP levels were not significantly reduced by l-NAME treatment, and no expression of inducible or neuronal NO synthase was noted in microvessels of eNOS-KO mice, suggesting an involvement of NO-independent mechanisms. Treatment with l-NAME caused an upregulation of vascular ACE and an increase in cardiac lucigenin chemiluminescence that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or CS866 (angiotensin II type 1 receptor antagonist) along with the suppression of vascular lesion formation.
  
  
  CONCLUSIONS
  These results provide the first direct evidence that the long-term vascular effects of l-NAME are not mediated by simple inhibition of endothelial NO synthesis. Direct upregulation of local ACE and increased oxidative stress appear to be involved in the long-term vascular effects of l-NAME in vivo.
authors.affiliation: Second Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Suda
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Morishita
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.forename: Masataka
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tasaki
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Nakashima
mesh_terms: D000166:Acridines; D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D003324:Coronary Artery Disease / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006152:Cyclic GMP / Q000378:metabolism; D018450:Disease Progression; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010084:Oxidation-Reduction; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D013995:Time
chemical_list: D000166:Acridines; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; C033472:10,10'-dimethyl-9,9'-biacridinium; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D007703:Peptidyl-Dipeptidase A; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester