title: Beneficial Effects of Sildenafil on Tissue Perfusion and Inflammation in a Murine Model of Limb Ischemia and Atherosclerosis.
abstract: BACKGROUND
  Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, has endothelium protective and angiogenic effects.
  
  
  OBJECTIVE
  To test if sildenafil improves tissue perfusion and neovascularization and downregulates proinflammatory molecules following limb ischemia.
  
  
  METHODS
  30 ApoE-/- male mice, bred with cholesterol rich diet for 4 weeks, were anesthetized and underwent unilateral hind-limb ischemia with ligation of the left femoral artery. Mice were randomized in 2 groups: sildenafil (1 mg/Kg for 7 days intraperitoneally, i.p.) or normal saline (0.4 ml for 7 days, i.p.). Bilateral hind-limb perfusion was estimated by laser Doppler imaging after surgery on days 0, 7 and 28.
  
  
  RESULTS
  Sildenafil significantly reduced at day 28 compared with day 0 levels of soluble intracellular adhesion molecule-1(sICAM-1) [2.24(1.81-2.41) vs. 1.29(0.87-1.45) ng/ml, p=0,01], soluble E-selectin (sE-Selectin) [5.52 (3.67-6.14) vs 1.71 (1.42-2.86) ng/ml, p=0.02] and tissue plasminogen activator inhibitor- 1 (tPAI-1) [0.13(0.07-0.21) vs 0.08 (0.04-0.10) ng/ml, p=0.01] while normal saline had no effect on the levels of sICAM-1, sE-Selectin and tPAI-1. Treatment with sildenafil was associated with increased perfusion in the ischemic limb compared with controls.
  
  
  CONCLUSIONS
  Sildenafil exerts significant beneficial effects on tissue perfusion and inflammatory status after limb ischemia, a finding implying neovascularization and potential vascular protective properties of sildenafil.
authors.affiliation: 1st Department of Cardiology, `Hippokration` Hospital, University of Athens, Medical School, Athens, Greece.
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Valatsou
authors.affiliation: 1st Department of Cardiology, `Hippokration` Hospital, University of Athens, Medical School, Athens, Greece.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Briasoulis
authors.affiliation: 1st Department of Cardiology, `Hippokration` Hospital, University of Athens, Medical School, Athens, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Vogiatzi
authors.affiliation: Laboratory for Experimental Surgery and Surgical Research, University of Athens, Medical School, Athens, Greece.
authors.forename: Alsistis
authors.initials: A
authors.lastname: Pantopoulou
authors.affiliation: Vasilissis Sofias 114, P.O. 115 28, Hippokration Hospital, University of Athens, Medical School, Athens, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Oikonomou
authors.affiliation: 1st Department of Cardiology, `Hippokration` Hospital, University of Athens, Medical School, Athens, Greece.
authors.forename: Antigoni
authors.initials: A
authors.lastname: Miliou
authors.affiliation: Laboratory for Experimental Surgery and Surgical Research, University of Athens, Medical School, Athens, Greece.
authors.forename: Despina
authors.initials: D
authors.lastname: Perrea
authors.affiliation: 1st Department of Cardiology, `Hippokration` Hospital, University of Athens, Medical School, Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tousoulis
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D001783:Blood Flow Velocity; D004195:Disease Models, Animal; D019040:E-Selectin / Q000097:blood; D006614:Hindlimb; D007249:Inflammation / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D007511:Ischemia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D000074085:Mice, Knockout, ApoE; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D012039:Regional Blood Flow; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D043925:Angiogenesis Inducing Agents; D000893:Anti-Inflammatory Agents; D019040:E-Selectin; C090509:Icam1 protein, mouse; D018836:Inflammation Mediators; D017395:Plasminogen Activator Inhibitor 1; D018799:Intercellular Adhesion Molecule-1; D000068677:Sildenafil Citrate
keywords: Sildenafil; ischemia; laser doppler; neovascularization; pro-inflammatory molecules