title: Endothelial nitric oxide synthase enhancer for protection of endothelial function from asymmetric dimethylarginine-induced injury in human internal thoracic artery.
abstract: OBJECTIVE
  Endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine is a cardiovascular risk factor that is elevated in patients with coronary artery disease. We hypothesized that novel endothelial nitric oxide synthase enhancer AVE3085 might improve the endothelial function altered by asymmetric dimethylarginine in the human internal thoracic artery.
  
  
  METHODS
  Cumulative concentration-relaxation curves to acetylcholine (-11 to -5 log mol/L) were established in left internal thoracic artery rings (n = 65) from 27 patients undergoing coronary artery bypass grafting in precontraction induced by U46619 (-8 log mol/L) in the absence or presence of asymmetric dimethylarginine (100 μmol/L) or AVE3085 (30 μmol/L). Protein expressions of endothelial nitric oxide synthase and levels of superoxide anion production were detected.
  
  
  RESULTS
  Maximal relaxation induced by acetylcholine was significantly attenuated by asymmetric dimethylarginine (12.7% ± 2.3% vs 35.3% ± 5.0% in control; P < .05) and significantly restored by AVE3085 (23.4% ± 2.8%; P < .05). AVE3085 also markedly restored endothelial nitric oxide synthase expression (0.29 ± 0.008; P = .012) reduced by asymmetric dimethylarginine (0.05 ± 0.04 vs 0.36 ± 0.03 in control; P = .014). Increased superoxide anion production by asymmetric dimethylarginine (2.97 ± 0.25 vs 0.51 ± 0.10 relative light units/[s/mg] in control; P < .05) was inhibited by AVE3805 (0.62 ± 0.104 relative light units/[s/mg]; P < .05).
  
  
  CONCLUSIONS
  AVE3085 may restore endothelium-dependent relaxation reduced by asymmetric dimethylarginine through upregulation of endothelial nitric oxide synthase expression and inhibition of production of superoxide anion in human internal thoracic artery. These findings provide new insights into endothelial protection of coronary bypass grafting vessels to improve long-term patency of grafts.
authors.affiliation: TEDA International Cardiovascular Hospital, Medical College, Nankai University, Tianjin, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Xuan
authors.forename: Feng-Jun
authors.initials: FJ
authors.lastname: Chang
authors.forename: Xiao-Cheng
authors.initials: XC
authors.lastname: Liu
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Bai
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Liao
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: He
authors.forename: Jing-Song
authors.initials: JS
authors.lastname: Ou
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000975:Antioxidants / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology*; D015153:Blotting, Western; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology*; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D008875:Middle Aged; D009213:Myography; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014654:Vascular Patency / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C528910:2,2-difluorobenzo(1,3)dioxole-5-carboxylic acid indan-2-ylamide; D000975:Antioxidants; D052117:Benzodioxoles; D020536:Enzyme Activators; D007189:Indans; D014665:Vasodilator Agents; D013481:Superoxides; C018524:N,N-dimethylarginine; D001120:Arginine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine