Abstract
IntroductionRecent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion injury. The aim of this study was to determine, by obtaining metabolic evidence from microdialysis, if sildenafil could reduce the severity of postresuscitation myocardial dysfunction and lead to cardioprotection through beneficial effects on energy metabolism.MethodsTwenty-four male piglets were randomly divided into three groups: sildenafil (n = 8), saline (SA; n = 8) and sham operation (n = 8). Sildenafil pretreatment consisted of 0.5 mg/kg sildenafil administered once intraperitoneally 30 minutes prior to ventricular fibrillation (VF). The myocardial interstitial fluid (ISF) concentrations of glucose, lactate, pyruvate, glutamate and glycerol were determined by microdialysis before VF. Afterward, the piglets were subjected to 8 minutes of untreated VF followed by 15 minutes of open-chest cardiopulmonary resuscitation. ISF was collected continuously, and the experiment was terminated 24 hours after resuscitation.ResultsAfter 8 minutes of untreated VF, the sildenafil group exhibited higher glucose and pyruvate concentrations of ISF and lower lactate and glutamate levels in comparison with the SA group, and these data reached statistical significance (P < 0.05). Advanced cardiac life support was delivered to both groups, with a 24-hour survival rate showing a promising trend in the sildenafil group (7 of 8 versus 3 of 8 survivors, P < 0.05). Compared with the SA group, the sildenafil group had a better outcome in terms of hemodynamic and oxygen metabolism parameters (P < 0.05). Myocardial tissue analysis revealed a dramatic increase in the contents of ATP, ADP and phosphocreatine in the sildenafil group versus the SA group at 24 hours after return of spontaneous circulation (ROSC; P = 0.03, P = 0.02 and P = 0.02, respectively). Furthermore, 24 hours after ROSC, the sildenafil group had marked elevations in activity of left ventricular Na+-K+-ATPase and Ca2+-ATPase compared with the SA group (P = 0.03, P = 0.04, respectively).ConclusionsSildenafil could reduce the severity of postresuscitation myocardial dysfunction, and it produced better clearance of metabolic waste in the ISF. This work might provide insights into the development of a novel strategy to treat postresuscitation myocardial dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0641-7) contains supplementary material, which is available to authorized users.
Highlights
Recent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion injury
In our analysis of the changes of interstitial fluid (ISF) metabolites during ventricular fibrillation (VF) and reperfusion, we observed that sildenafil inhibited abrupt increases in ISF lactate and glutamate levels, which indicates that sildenafil could improve myocardial energy metabolism during ischemia and reperfusion
We found that the activities of Na+-K+-ATPase and Ca2+-ATPase were significantly increased in the sildenafil group compared with the SA group at 24 hours after return of spontaneous circulation (ROSC), and we found that the contents of ATP, ADP and phosphodiesterase in the SA group were much lower than in the sildenafil group, indicating greater energy exhaustion in the SA group, which indicated that the myocardium energy metabolism system was damaged much more severely in the SA group than in the sildenafil group
Summary
Recent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion injury. The aim of this study was to determine, by obtaining metabolic evidence from microdialysis, if sildenafil could reduce the severity of postresuscitation myocardial dysfunction and lead to cardioprotection through beneficial effects on energy metabolism. In patients who initially achieve return of spontaneous circulation (ROSC) after CA, the significant subsequent morbidity and mortality are largely due to the myocardial dysfunction that accompanies prolonged whole-body ischemia. Welltolerated for long-term treatment with few side effects, sildenafil reduces pulmonary vascular resistance, improves arterial oxygenation in patients with pulmonary artery hypertension and prevents altitude-induced hypoxemia [7,8]; the potential role of sildenafil as a novel pharmacologic adjunct to resuscitation from CA for the purpose of attenuating the myocardial dysfunction caused by I/R injury remains unexplored
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