title: Sildenafil restores endothelial function in the apolipoprotein E knockout mouse.
abstract: BACKGROUND
  Atherosclerosis is an inflammatory process of the arterial walls and is initiated by endothelial dysfunction accompanied by an imbalance in the production of reactive oxygen species (ROS) and nitric oxide (NO). Sildenafil, a selective phosphodiesterase-5 (PDE5) inhibitor used for erectile dysfunction, exerts its cardiovascular effects by enhancing the effects of NO. The aim of this study was to investigate the influence of sildenafil on endothelial function and atherosclerosis progression in apolipoprotein E knockout (apoE-/-) mice.
  
  
  METHODS
  ApoE-/- mice treated with sildenafil (Viagra®, 40 mg/kg/day, for 3 weeks, by oral gavage) were compared to the untreated apoE-/- and the wild-type (WT) mice.Aortic rings were used to evaluate the relaxation responses to acetylcholine (ACh) in all of the groups. In a separate set of experiments, the roles of NO and ROS in the relaxation response to ACh were evaluated by incubating the aortic rings with L-NAME (NO synthase inhibitor) or apocynin (NADPH oxidase inhibitor). In addition, the atherosclerotic lesions were quantified and superoxide production was assessed.
  
  
  RESULTS
  Sildenafil restored the vasodilator response to acetylcholine (ACh) in the aortic rings of the apoE-/- mice. Treatment with L-NAME abolished the vasodilator responses to ACh in all three groups of mice and revealed an augmented participation of NO in the endothelium-dependent vasodilation in the sildenafil-treated animals. The normalized endothelial function in sildenafil-treated apoE-/- mice was unaffected by apocynin highlighting the low levels of ROS production in these animals. Moreover, morphological analysis showed that sildenafil treatment caused approximately a 40% decrease in plaque deposition in the aorta.
  
  
  CONCLUSIONS
  This is the first study demonstrating the beneficial effects of chronic treatment with sildenafil on endothelial dysfunction and atherosclerosis in a model of spontaneous hypercholesterolemia. These data indicate that the main mechanism of the beneficial effect of sildenafil on the endothelial function appears to involve an enhancement of the NO pathway along with a reduction in oxidative stress.
authors.affiliation: Dept, of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil.
authors.forename: Camille M
authors.initials: CM
authors.lastname: Balarini
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Leal
authors.forename: Isabele B S
authors.initials: IB
authors.lastname: Gomes
authors.forename: Thiago M C
authors.initials: TM
authors.lastname: Pereira
authors.forename: Agata L
authors.initials: AL
authors.lastname: Gava
authors.forename: Silvana S
authors.initials: SS
authors.lastname: Meyrelles
authors.forename: Elisardo C
authors.initials: EC
authors.lastname: Vasquez
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D001057:Apolipoproteins E; D010879:Piperazines; D011687:Purines; D017382:Reactive Oxygen Species; D013450:Sulfones; D009569:Nitric Oxide; C056165:acetovanillone; D000068677:Sildenafil Citrate; D019331:NG-Nitroarginine Methyl Ester