Asymmetric dimethylarginine produces vascular lesions in endothelial nitric oxide synthase-deficient mice: involvement of renin-angiotensin system and oxidative stress.
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.
Suda
Osamu
O
Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Tsutsui
Masato
M
Morishita
Tsuyoshi
T
Tasaki
Hiromi
H
Ueno
Susumu
S
Nakata
Sei
S
Tsujimoto
Takashi
T
Toyohira
Yumiko
Y
Hayashida
Yoshiaki
Y
Sasaguri
Yasuyuki
Y
Ueta
Yoichi
Y
Nakashima
Yasuhide
Y
Yanagihara
Nobuyuki
N
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
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