title: Phosphodiesterase-5 inhibition mimics intermittent reoxygenation and improves cardioprotection in the hypoxic myocardium.
abstract: Although chronic hypoxia is a claimed myocardial risk factor reducing tolerance to ischemia/reperfusion (I/R), intermittent reoxygenation has beneficial effects and enhances heart tolerance to I/R.
  
  
  OBJECTIVE
  To test the hypothesis that, by mimicking intermittent reoxygenation, selective inhibition of phosphodiesterase-5 activity improves ischemia tolerance during hypoxia. Adult male Sprague-Dawley rats were exposed to hypoxia for 15 days (10% O₂) and treated with placebo, sildenafil (1.4 mg/kg/day, i. p.), intermittent reoxygenation (1 h/day exposure to room air) or both. Controls were normoxic hearts. To assess tolerance to I/R all hearts were subjected to 30-min regional ischemia by left anterior descending coronary artery ligation followed by 3 h-reperfusion. Whereas hypoxia depressed tolerance to I/R, both sildenafil and intermittent reoxygenation reduced the infarct size without exhibiting cumulative effects. The changes in myocardial cGMP, apoptosis (DNA fragmentation), caspase-3 activity (alternative marker for cardiomyocyte apoptosis), eNOS phosphorylation and Akt activity paralleled the changes in cardioprotection. However, the level of plasma nitrates and nitrites was higher in the sildenafil+intermittent reoxygenation than sildenafil and intermittent reoxygenation groups, whereas total eNOS and Akt proteins were unchanged throughout.
  
  
  CONCLUSIONS
  Sildenafil administration has the potential to mimic the cardioprotective effects led by intermittent reoxygenation, thereby opening the possibility to treat patients unable to be reoxygenated through a pharmacological modulation of NO-dependent mechanisms.
authors.affiliation: Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. giuseppina.milano@chuv.ch
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Milano
authors.forename: Paola
authors.initials: P
authors.lastname: Bianciardi
authors.forename: Viviane
authors.initials: V
authors.lastname: Rochemont
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vassalli
authors.forename: Ludwig K von
authors.initials: LK
authors.lastname: Segesser
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Corno
authors.forename: Marco
authors.initials: M
authors.lastname: Guazzi
authors.forename: Michele
authors.initials: M
authors.lastname: Samaja
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D011086:Polycythemia / Q000097:blood / Q000150:complications / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D058986:Phosphodiesterase 5 Inhibitors; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D010100:Oxygen