title: ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins.
abstract: OBJECTIVE
  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 microg; 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 micromol/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 micromol/l) and reducing the oxidative stress by lowering urinary 8-iso-prostaglandin F(2alpha) (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.
authors.affiliation: Department of Cardiology, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. sydow@uke.uni-hamburg.de
authors.forename: Karsten
authors.initials: K
authors.lastname: Sydow
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: Naoshi
authors.initials: N
authors.lastname: Arakawa
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Bode-Böger
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsikas
authors.forename: Burkhard
authors.initials: B
authors.lastname: Hornig
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Frölich
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D001157:Arterial Occlusive Diseases / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000627:therapeutic use; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D016491:Peripheral Vascular Diseases / Q000097:blood / Q000188:drug therapy; D014805:Vitamin B 12 / Q000097:blood / Q000627:therapeutic use; D025101:Vitamin B 6 / Q000097:blood / Q000627:therapeutic use; D014815:Vitamins / Q000627:therapeutic use*
chemical_list: D014815:Vitamins; C018524:N,N-dimethylarginine; D025101:Vitamin B 6; D005492:Folic Acid; D001120:Arginine; D019001:Nitric Oxide Synthase; D014805:Vitamin B 12