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EnglishAlthough 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% O(2)) 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
| Titolo: | Phosphodiesterase-5 inhibition mimics intermittent reoxygenation and improves cardioprotection in the hypoxic myocardium |
| Autori: | BIANCIARDI, PAOLA ROSANNA MARIA (Secondo) GUAZZI, MARCO (Penultimo) |
| Parole Chiave: | Polycythemia ; Animals ; Phosphodiesterase 5 Inhibitors ; Apoptosis ; Cardiotonic Agents ; Proto-Oncogene Proteins c-akt ; Cell Hypoxia ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Rats ; Body Weight ; Nitric Oxide ; Oxygen ; Rats, Sprague-Dawley ; Nitric Oxide Synthase Type III ; Cardiomegaly ; Myocardial Infarction ; Signal Transduction ; Male ; Myocardium |
| Settore Scientifico Disciplinare: | Settore BIO/10 - Biochimica Settore MED/11 - Malattie dell'Apparato Cardiovascolare |
| Data di pubblicazione: | 2011 |
| Rivista: | |
| Tipologia: | Article (author) |
| Digital Object Identifier (DOI): | 10.1371/journal.pone.0027910 |
| Appare nelle tipologie: | 01 - Articolo su periodico |
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| File | Descrizione | Tipologia | Licenza | |
|---|---|---|---|---|
| 127-12PONE-silde_mimic.pdf | Publisher's version/PDF | Open Access Visualizza/Apri |
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