Under certain conditions, NO synthesis is disturbed, and this may contribute to the progression of atherosclerosis, and impair angiogenic response. The impairment of the NO synthase pathway may be due in part to an endogenous NOS inhibitor ADMA (asymmetric dimethylarginine). In patients with peripheral arterial disease (PAD), ADMA levels are elevated. In these individuals L-arginine enhances NO synthesis and improves limb blood flow. Our proposal is designed to determine if chronic administration of L-arginine will cause a sustained enhancement of limb blood flow, and will reduce symptoms in individuals with PAD. We will also determine if these effects are accompanied by anti- atherogenic and/or pro-angiogenic effects of NO biosynthesis. Patients with PAD will be entered into a randomized placebo-controlled clinical trial to assess the effects of L-arginine upon functional status (treadmill exercise testing; quality of life) and limb blood (by mercury strain gauge plethysmography). We will determine if NO biosynthesis is involved in the effects of L-arginine by: function of duplex ultrasonography of flow-mediated vasodilation. We will assess limb hemodynamics (by Doppler-derived pressures, plethysmography, and by MR perfusion imaging), conduit vessel structure (using magnetic resonance angiography); and evidence of angiogenesis using novel MR algorithms (to include flow-independent imaging, manipulation, manipulation of 3-dimensional data sets, and use of oxygen saturation effects on T2 relaxation time). These studies will determine if prolonged L-arginine treatment may have effects upon vascular structure, lesion size and/or angiogenesis. These studies may lead to a novel and cost-effective strategy for treatment of peripheral arterial disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL063685-01
Application #
6024041
Study Section
Special Emphasis Panel (ZRG1-CCVS (01))
Project Start
2000-02-01
Project End
2004-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$360,666
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Maxwell, Andrew J; Niebauer, Josef; Lin, Patrick S et al. (2009) Hypercholesterolemia impairs exercise capacity in mice. Vasc Med 14:249-57
Potena, Luciano; Fearon, William F; Sydow, Karsten et al. (2008) Asymmetric dimethylarginine and cardiac allograft vasculopathy progression: modulation by sirolimus. Transplantation 85:827-33
Sydow, Karsten; Mondon, Carl E; Schrader, Joerg et al. (2008) Dimethylarginine dimethylaminohydrolase overexpression enhances insulin sensitivity. Arterioscler Thromb Vasc Biol 28:692-7
Fung, Eric T; Wilson, Andrew M; Zhang, Fujun et al. (2008) A biomarker panel for peripheral arterial disease. Vasc Med 13:217-24
Xu, Lijun; Wang, Bingyin; Kaur, Kirandeep et al. (2007) NOx and ADMA changes with focal ischemia, amelioration with the chaperonin GroEL. Neurosci Lett 418:201-4
Cooke, John P (2007) Angiogenesis and the role of the endothelial nicotinic acetylcholine receptor. Life Sci 80:2347-51
Wilson, Andrew M; Kimura, Eiichiro; Harada, Randall K et al. (2007) Beta2-microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies. Circulation 116:1396-403
Wilson, Andrew M; Harada, Randall; Nair, Nandini et al. (2007) L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. Circulation 116:188-95
Knowles, Joshua W; Assimes, Themistocles L; Li, Jun et al. (2007) Genetic susceptibility to peripheral arterial disease: a dark corner in vascular biology. Arterioscler Thromb Vasc Biol 27:2068-78
Konishi, Hakuoh; Sydow, Karsten; Cooke, John P (2007) Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury. J Am Coll Cardiol 49:1099-105

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