Article: article from journal or magazin.
Phosphodiesterase-5 inhibition mimics intermittent reoxygenation and improves cardioprotection in the hypoxic myocardium.
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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. AIM OF THE STUDY: 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.
Animals, Apoptosis/drug effects, Body Weight/drug effects, Cardiomegaly/blood, Cardiomegaly/complications, Cardiotonic Agents/pharmacology, Cell Hypoxia/drug effects, Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism, Male, Myocardial Infarction/blood, Myocardial Infarction/complications, Myocardium/enzymology, Myocardium/pathology, Nitric Oxide/blood, Nitric Oxide Synthase Type III/metabolism, Oxygen/metabolism, Phosphodiesterase 5 Inhibitors/pharmacology, Polycythemia/blood, Polycythemia/complications, Proto-Oncogene Proteins c-akt/metabolism, Rats, Rats, Sprague-Dawley, Signal Transduction/drug effects
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