© 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