Phosphodiesterase-5 inhibition mimics intermittent reoxygenation and improves cardioprotection in the hypoxic myocardium.

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Serval ID
serval:BIB_071AE3CEB695
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Phosphodiesterase-5 inhibition mimics intermittent reoxygenation and improves cardioprotection in the hypoxic myocardium.
Journal
Plos One
Author(s)
Milano G., Bianciardi P., Rochemont V., Vassalli G., Segesser L.K., Corno A.F., Guazzi M., Samaja M.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2011
Volume
6
Number
11
Pages
e27910
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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. 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.
Keywords
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
Pubmed
Web of science
Open Access
Yes
Create date
06/06/2012 17:50
Last modification date
20/08/2019 12:29
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