© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins
aDepartment of Cardiology, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
bInstitute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
cDepartment of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
dInstitute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
* Corresponding author. Tel.: +49-40-4280-36575; fax: +49-40-4280-38862. sydow{at}uke.uni-hamburg.de
* The term ‘hyperhomocyst(e)inemia’ is used in this paper to indicate that plasma homocysteine assays measure the total concentration of thiol, disulfide, and mixed disulfide adducts of homocysteine.
Objectives: Hyperhomocyst(e)inemia is a risk factor for atherosclerotic vascular disease, and it is associated with endothelial dysfunction. Mechanisms responsible for endothelial dysfunction in hyperhomocyst(e)inemia may involve impaired bioavailability of NO, possibly secondary to accumulation of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) and increased oxidative stress. We investigated whether oral treatment with B vitamins or L-arginine normalizes endothelium-dependent, flow-dependent vasodilation (FDD) in patients with peripheral arterial occlusive disease (PAOD) and hyperhomocyst(e)inemia. Methods: 27 patients with PAOD and hyperhomocyst(e)inemia were assigned to oral treatment with combined B vitamins (folate, 10 mg; vitamin B-12, 200 µg; vitamin B-6, 20 mg/day), L-arginine (24 g/day) or placebo, for 8 weeks in a double-blind fashion. FDD was determined by high-resolution ultrasound in the radial artery. Results: Vitamin B supplementation significantly lowered plasma homocyst(e)ine concentration from 15.8±1.8 to 8.7±1.1 µmol/l (P<0.01). However, B vitamins had no significant effect on FDD (baseline, 7.8±0.7%, B vitamins, 8.3±0.9%, placebo 8.9±0.7%; P = n.s.). In contrast, L-arginine treatment did not affect homocyst(e)ine levels, but significantly improved FDD (10.2±0.2%), probably by antagonizing the impact of elevated ADMA concentration (3.8±0.3 µmol/l) and reducing the oxidative stress by lowering urinary 8-iso-prostaglandin F2
(baseline, 76.3±7.1 vs. 62.7±8.3 pmol/mmol creatinine after 8 weeks). Conclusions: Oral supplementation with combined B vitamins during 8 weeks does not improve endothelium-dependent vasodilation in PAOD patients with hyperhomocyst(e)inemia, whereas L-arginine significantly improved endothelial function in these patients. Thus, accumulation of ADMA and increased oxidative stress may underlie endothelial dysfunction under hyperhomocyst(e)inemic conditions. These findings may have importance for evaluation of homocyst(e)ine-lowering therapy.
KEYWORDS Atherosclerosis; Endothelial function; Nitric oxide
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F. Palm, M. L. Onozato, Z. Luo, and C. S. Wilcox Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3227 - H3245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. de Bree, L. A van Mierlo, and R. Draijer Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials Am. J. Clinical Nutrition, September 1, 2007; 86(3): 610 - 617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K Rudolph, K. Ruempler, E. Schwedhelm, J. Tan-Andresen, U. Riederer, R. H Boger, and R. Maas Acute effects of various fast-food meals on vascular function and cardiovascular disease risk markers: the Hamburg Burger Trial Am. J. Clinical Nutrition, August 1, 2007; 86(2): 334 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Antoniades, D. Tousoulis, K. Marinou, C. Vasiliadou, C. Tentolouris, G. Bouras, C. Pitsavos, and C. Stefanadis Asymmetrical dimethylarginine regulates endothelial function in methionine-induced but not in chronic homocystinemia in humans: effect of oxidative stress and proinflammatory cytokines. Am. J. Clinical Nutrition, October 1, 2006; 84(4): 781 - 788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Tyagi, K. C. Sedoris, M. Steed, A. V. Ovechkin, K. S. Moshal, and S. C. Tyagi Mechanisms of homocysteine-induced oxidative stress Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2649 - H2656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hayashi, P. A. R. Juliet, H. Matsui-Hirai, A. Miyazaki, A. Fukatsu, J. Funami, A. Iguchi, and L. J. Ignarro L-citrulline and L-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits PNAS, September 20, 2005; 102(38): 13681 - 13686. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tanaka, K. Sydow, F. Gunawan, J. Jacobi, P. S. Tsao, R. C. Robbins, and J. P. Cooke Dimethylarginine Dimethylaminohydrolase Overexpression Suppresses Graft Coronary Artery Disease Circulation, September 13, 2005; 112(11): 1549 - 1556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Schnabel, S. Blankenberg, E. Lubos, K. J. Lackner, H. J. Rupprecht, C. Espinola-Klein, N. Jachmann, F. Post, D. Peetz, C. Bickel, et al. Asymmetric Dimethylarginine and the Risk of Cardiovascular Events and Death in Patients With Coronary Artery Disease: Results from the AtheroGene Study Circ. Res., September 2, 2005; 97(5): e53 - e59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Munzel, A. Daiber, V. Ullrich, and A. Mulsch Vascular Consequences of Endothelial Nitric Oxide Synthase Uncoupling for the Activity and Expression of the Soluble Guanylyl Cyclase and the cGMP-Dependent Protein Kinase Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1551 - 1557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H Boger Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials Vascular Medicine, July 1, 2005; 10(1_suppl): S19 - S25. [Abstract] [PDF]
|
|
|
|
|
|
S. Dayal and S. R Lentz ADMA and hyperhomocysteinemia Vascular Medicine, July 1, 2005; 10(1_suppl): S27 - S33. [Abstract] [PDF]
|
|
|
|
|
|
R. Maas Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA) Vascular Medicine, July 1, 2005; 10(1_suppl): S49 - S57. [Abstract] [PDF]
|
|
|
|
|
|
R. H Boger Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials Vascular Medicine, May 1, 2005; 10(2_suppl): S19 - S25. [Abstract] [PDF]
|
|
|
|
|
|
S. Dayal and S. R Lentz ADMA and hyperhomocysteinemia Vascular Medicine, May 1, 2005; 10(2_suppl): S27 - S33. [Abstract] [PDF]
|
|
|
|
|
|
R. Maas Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA) Vascular Medicine, May 1, 2005; 10(2_suppl): S49 - S57. [Abstract] [PDF]
|
|
|
|
|
|
C. Yan, A. Huang, Z. Wu, P. M. Kaminski, M. S. Wolin, T. H. Hintze, G. Kaley, and D. Sun Increased superoxide leads to decreased flow-induced dilation in resistance arteries of Mn-SOD-deficient mice Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2225 - H2231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ziegler, F. Mittermayer, C. Plank, E. Minar, M. Wolzt, and G.-H. Schernthaner Homocyst(e)ine-Lowering Therapy Does Not Affect Plasma Asymmetrical Dimethylarginine Concentrations in Patients with Peripheral Artery Disease J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2175 - 2178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. West, A. Likos-Krick, P. Brown, and F. Mariotti Oral L-Arginine Improves Hemodynamic Responses to Stress and Reduces Plasma Homocysteine in Hypercholesterolemic Men J. Nutr., February 1, 2005; 135(2): 212 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Scalera, J. Borlak, B. Beckmann, J. Martens-Lobenhoffer, T. Thum, M. Tager, and S. M. Bode-Boger Endogenous Nitric Oxide Synthesis Inhibitor Asymmetric Dimethyl L-Arginine Accelerates Endothelial Cell Senescence Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): 1816 - 1822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. Boger Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, Explains the "L-Arginine Paradox" and Acts as a Novel Cardiovascular Risk Factor J. Nutr., October 1, 2004; 134(10): 2842S - 2847S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Tsuda, I. Nishio, P. J. Kelly, and K. L. Furie Homocysteine, Vitamin B6, and Endothelial Dysfunction in Circulatory Disorders * Response Stroke, August 1, 2004; 35(8): 1785 - 1785. [Full Text] [PDF]
|
|
|
|
 |
|
 I. V. Smirnova, T. Sawamura, and M. S. Goligorsky Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency Am J Physiol Renal Physiol, July 1, 2004; 287(1): F25 - F32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sydow, B. Hornig, N. Arakawa, S. M Bode-Boger, D. Tsikas, T. Munuzel, and R. H Boger Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA Vascular Medicine, May 1, 2004; 9(2): 93 - 101. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Viswanathan, B. D. Hammock, J. W. Newman, P. Meerarani, M. Toborek, and B. Hennig Involvement of CYP 2C9 in Mediating the Proinflammatory Effects of Linoleic Acid in Vascular Endothelial Cells J. Am. Coll. Nutr., December 1, 2003; 22(6): 502 - 510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H Boger The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor Cardiovasc Res, October 1, 2003; 59(4): 824 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Cooke, K. Sydow, J. Chen, and P. Huang A Peculiar Result and a Fanciful Hypothesis Regarding L-Arginine * Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1128 - 1128. [Full Text] [PDF]
|
|