title: Sildenafil prevents endothelial dysfunction induced by ischemia and reperfusion via opening of adenosine triphosphate-sensitive potassium channels: a human in vivo study.
abstract: BACKGROUND
  Animal studies have demonstrated that administration of sildenafil can limit myocardial damage induced by prolonged ischemia, an effect that appears to be mediated by opening of adenosine triphosphate-sensitive potassium (K(ATP)) channels. No study has investigated whether sildenafil can also prevent the impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) in humans.
  
  
  RESULTS
  In a double-blind, placebo-controlled, crossover design, 10 healthy male volunteers (25 to 45 years old) were randomized to oral sildenafil (50 mg) or placebo. Two hours later, endothelium-dependent, flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). Seven days later, subjects received the other treatment (ie, placebo or sildenafil) and underwent the same protocol. Pre-IR radial artery diameter and FMD, as well as baseline radial artery diameter after IR, were similar between visits (P=NS). After placebo administration, IR significantly blunted FMD (before IR: 7.9+/-1.1%; after IR: 1.2+/-0.7%, P<0.01). Importantly, sildenafil limited this impairment in endothelium-dependent vasodilatation (before IR: 7.0+/-0.9%; after IR: 6.2+/-1.1%, P=NS; P<0.01 compared with placebo). In a separate protocol, this protective effect was completely prevented by previous administration of the sulfonylurea glibenclamide (glyburide, 5 mg), a blocker of K(ATP) channels (n=7; FMD before IR: 10.3+/-1.5%; after IR: 1.3+/-1.4%, P<0.05).
  
  
  CONCLUSIONS
  In humans, oral sildenafil induces potent protection against IR-induced endothelial dysfunction through opening of K(ATP) channels. Further studies are needed to test the potential clinical implications of this finding.
authors.affiliation: Department of Internal, Cardiovascular, and Geriatric Medicine, Azienda Universitaria Ospedaliera Senese, Siena, Italy. tommaso.gori@utoronto.ca
authors.forename: Tommaso
authors.initials: T
authors.lastname: Gori
authors.forename: Silvia
authors.initials: S
authors.lastname: Sicuro
authors.forename: Saverio
authors.initials: S
authors.lastname: Dragoni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Donati
authors.forename: Sandro
authors.initials: S
authors.lastname: Forconi
authors.forename: John D
authors.initials: JD
authors.lastname: Parker
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D015990:Placebo Effect; D015221:Potassium Channels / Q000378:metabolism; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones
chemical_list: D010879:Piperazines; D015221:Potassium Channels; D011687:Purines; D013450:Sulfones; C117780:mitochondrial K(ATP) channel; D000068677:Sildenafil Citrate; D005905:Glyburide