title: Asymmetric dimethylarginine produces vascular lesions in endothelial nitric oxide synthase-deficient mice: involvement of renin-angiotensin system and oxidative stress.
abstract: OBJECTIVE
  Asymmetric dimethylarginine (ADMA) is widely believed to be an endogenous nitric oxide synthase (eNOS) inhibitor. However, in this study, we examined our hypothesis that the long-term vascular effects of ADMA are not mediated by inhibition of endothelial NO synthesis.
  
  
  RESULTS
  ADMA was infused in wild-type and eNOS-knockout (KO) mice by osmotic minipump for 4 weeks. In wild-type mice, long-term treatment with ADMA caused significant coronary microvascular lesions. Importantly, in eNOS-KO mice, treatment with ADMA also caused an extent of coronary microvascular lesions that was comparable to that in wild-type mice. These vascular effects of ADMA were not prevented by supplementation of l-arginine, and vascular NO production was not reduced by ADMA treatment. Treatment with ADMA caused upregulation of angiotensin-converting enzyme (ACE) and an increase in superoxide production that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or olmesartan (AT(1) receptor antagonist), which simultaneously suppressed vascular lesion formation.
  
  
  CONCLUSIONS
  These results provide the first direct evidence that the long-term vascular effects of ADMA are not solely mediated by simple inhibition of endothelial NO synthesis. Direct upregulation of ACE and increased oxidative stress through AT(1) receptor appear to be involved in the long-term vascular effects of ADMA in vivo. This study demonstrates that asymmetrical dimethylarginine (ADMA) causes arteriosclerotic coronary lesions in mice in vivo through mechanisms other than simple inhibition of endothelial NO synthesis. Our findings should contribute to a better understanding of the pathophysiological role of ADMA in arteriosclerosis.
authors.affiliation: Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, 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: Hiromi
authors.initials: H
authors.lastname: Tasaki
authors.forename: Susumu
authors.initials: S
authors.lastname: Ueno
authors.forename: Sei
authors.initials: S
authors.lastname: Nakata
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsujimoto
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Toyohira
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Hayashida
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ueta
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000633:toxicity*; D003327:Coronary Disease / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D004790:Enzyme Induction / Q000187:drug effects; D006710:Homocysteine / Q000097:blood; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D015918:Infusion Pumps, Implantable; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000378:metabolism; D000068557:Olmesartan Medoxomil; D018384:Oxidative Stress; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D013841:Thiazepines / Q000494:pharmacology / Q000627:therapeutic use; D019323:omega-N-Methylarginine / Q000633:toxicity
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D009566:Nitrates; D009573:Nitrites; D013777:Tetrazoles; D013841:Thiazepines; D006710:Homocysteine; D013481:Superoxides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D000068557:Olmesartan Medoxomil; C055603:temocapril hydrochloride; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D007703:Peptidyl-Dipeptidase A; D019331:NG-Nitroarginine Methyl Ester