title: Effect of silibinin on endothelial dysfunction and ADMA levels in obese diabetic mice.
abstract: BACKGROUND
  Cardiovascular diseases (CVD) in diabetic patients have endothelial dysfunction as a key pathogenetic event. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), plays a pivotal role in endothelial dysfunction. Different natural polyphenols have been shown to preserve endothelial function and prevent CVD. In this study, we assessed the effect of silibinin, a widely used flavonolignan from milk thistle, on ADMA levels and endothelial dysfunction in db/db mice.
  
  
  METHODS
  Eight-week-old db/db mice were administrated a 20 mg/Kg i.p. daily dose of silibinin (n = 6) or vehicle (n = 6) for four weeks. Heterozygous lean db/m mice served as control. Plasma, aorta and liver ADMA levels were determined by ELISA. Vascular reactivity to phenilephrine (PE), acetylcholine (ACh), sodium nitroprusside (SNP) and ADMA was assessed in isolated aortic segments, in wire myograph.
  
  
  RESULTS
  Plasma and aorta ADMA levels were higher in db/db than in control lean mice. Silibinin administration markedly decreased plasma ADMA; consistently, aorta ADMA was reduced in silibinin-treated animals. Plasma and aorta ADMA levels exhibited a positive correlation, whereas liver ADMA was inversely correlated with both plasma and aorta ADMA concentrations. Endothelium-(NO)-dependent vasodilatation to ACh was impaired in db/db mice and was restored in the silibinin group, in accordance with the observed reduction of plasma and vascular levels of ADMA. Endothelium-independent vasodilatation to SNP was not modified by silibinin administration; contractile tone induced in isolated aorta from db/db mice by challenging with exogenous ADMA was not affected by the treatment.
  
  
  CONCLUSIONS
  Silibinin markedly improves endothelial dysfunction in db/db mice by reducing circulating and vascular ADMA levels. Clinical studies are warranted to assess the efficacy of silibinin for cardiovascular protection.
authors.affiliation: Department of Internal Medicine, University of Catania, Catania, Italy. federicosalamone@yahoo.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Li Volti
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salomone
authors.forename: Valeria
authors.initials: V
authors.lastname: Sorrenti
authors.forename: Andrea
authors.initials: A
authors.lastname: Mangiameli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Urso
authors.forename: Ilias
authors.initials: I
authors.lastname: Siarkos
authors.forename: Fabio
authors.initials: F
authors.lastname: Galvano
authors.forename: Federico
authors.initials: F
authors.lastname: Salamone
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009599:Nitroprusside / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology*; D010656:Phenylephrine / Q000494:pharmacology; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D012838:Silymarin; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; D000077385:Silybin; C018524:N,N-dimethylarginine; D001120:Arginine; D000109:Acetylcholine