title: Insights into the effect of nitric oxide and its metabolites nitrite and nitrate at inhibiting neointimal hyperplasia.
abstract: OBJECTIVE
  Periadventitial delivery of the nitric oxide (NO) donor PROLI/NO following arterial injury effectively inhibits neointimal hyperplasia. Given the short half-life of NO release from PROLI/NO, our goal was to determine if inhibition of neointimal hyperplasia by PROLI/NO was due to NO, or its metabolites nitrite and nitrate.
  
  
  RESULTS
  In vitro, the NO donor DETA/NO inhibited proliferation of rat aortic vascular smooth muscle cells (RASMC), but neither nitrite nor nitrate did. In vivo, following rat carotid artery balloon injury or injury plus the molar equivalents of PROLI/NO, nitrite, or nitrate (n=8-11/group), PROLI/NO was found to provide superior inhibition of neointimal hyperplasia (82% inhibition of intimal area, and 44% inhibition of medial area, p<0.001). Only modest inhibition was noted with nitrite or nitrate (45% and 41% inhibition of intimal area, and 31% and 29% inhibition of medial area, respectively, p<0.001). No effects on blood pressure were noted with any treatment groups. In vivo, only PROLI/NO inhibited cellular proliferation and increased arterial lumen area compared to injury alone (p<0.001). However, all three treatments inhibited inflammation (p<0.001).
  
  
  CONCLUSIONS
  PROLI/NO was more effective at inhibiting neointimal hyperplasia following arterial injury than nitrite or nitrate. However, modest inhibition of neointimal hyperplasia was observed with nitrite and nitrate, likely secondary to anti-inflammatory actions. In conclusion, we have demonstrated that the efficacy of NO donors is primarily due to NO production and not its metabolites, nitrite and nitrate.
authors.affiliation: Division of Vascular Surgery, and Institute for BioNanotechnology in Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States.
authors.forename: Ashley K
authors.initials: AK
authors.lastname: Vavra
authors.forename: George E
authors.initials: GE
authors.lastname: Havelka
authors.forename: Janet
authors.initials: J
authors.lastname: Martinez
authors.forename: Vanessa R
authors.initials: VR
authors.lastname: Lee
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiang
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
authors.forename: Melina R
authors.initials: MR
authors.lastname: Kibbe
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006965:Hyperplasia / Q000517:prevention & control*; D008297:Male; D058426:Neointima / Q000473:pathology* / Q000517:prevention & control*; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide