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.
Highlights
Systemic hypoxia, or insufficient supply of O2 to tissues, is a common denominator in several diseases, including myocardial infarction, cyanotic congenital heart defects, pulmonary obstructive diseases and chronic cor pulmonale
All of which reflect into systemic hypoxia, infants and children with congenital cyanotic heart defects represent a large population affected by the deleterious consequences of chronic systemic hypoxia
This study aims at testing the hypothesis that sildenafil administration during systemic hypoxia mimics the beneficial effects led by IntReox
Summary
Insufficient supply of O2 to tissues, is a common denominator in several diseases, including myocardial infarction, cyanotic congenital heart defects, pulmonary obstructive diseases and chronic cor pulmonale. In facts, when exposed to chronic systemic hypoxia without reoxygenation, hearts exhibit marked deleterious alterations in several signaling paths, including K+ATP channels [1], oxidative stress [2] and mitogen-activated protein kinases [3]. Such changes are followed by right ventricle dilatation with wall thickening [4], impaired tolerance to reoxygenation [2] and impaired ability to resist ischemia/ reperfusion (I/R) injury [5]. These findings are corroborated by the clinical observation that the outcome of surgery aimed at repairing the cyanotic congenital heart defects is complicated by myocardial damage occurring because of the acute re-oxygenation at the moment of the institution of cardiopulmonary bypass with elevated oxygen content, followed by the I/R injury when heart is arrested to perform the intra-cardiac repair [6]
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