Zoniporide preserves left ventricular compliance during ventricular fibrillation and minimizes postresuscitation myocardial dysfunction through benefits on energy metabolism
ABSTRACT To investigate whether sodium-hydrogen exchanger isoform-1 (NHE-1) inhibition attenuates myocardial injury during resuscitation from ventricular fibrillation through effects on energy metabolism, using an open-chest pig model in which coronary perfusion was controlled by extracorporeal circulation.
Randomized controlled animal study.
University research laboratory.
Male domestic pigs.
Ventricular fibrillation was electrically induced and left untreated for 8 mins, after which extracorporeal circulation was started and its flow adjusted to maintain a coronary perfusion pressure of 10 mm Hg. After 10 mins of extracorporeal circulation, restoration of spontaneous circulation was attempted by epicardial defibrillation and gradual reduction in extracorporeal flow. Two groups of eight pigs each were randomized to receive the NHE-1 inhibitor zoniporide (3 mg.kg-1) or vehicle control immediately before starting extracorporeal circulation.
Identical extracorporeal flows (approximately = 9% of baseline cardiac index) were required in zoniporide and control groups to attain the target coronary perfusion pressure, resulting in comparable left anterior descending coronary artery blood flow (9 +/- 1 and 10 +/- 1 mL.min-1) and resistance (0.10 +/- 0.01 and 0.10 +/- 0.01 dyne.sec.cm(-5)). Yet zoniporide prevented reductions in left ventricular volume and wall thickening while favoring higher myocardial creatine phosphate to creatine ratios (0.14 +/- 0.03 vs. 0.06 +/- 0.01, p < .05), lower myocardial adenosine (0.7 +/- 0.1 vs. 1.3 +/- 0.2, p < .05), and lower myocardial lactate (80 +/- 9 vs. 125 +/- 6 mmol.kg-1, p < .001). Postresuscitation, zoniporide-treated pigs had higher left ventricular ejection fraction (0.57 +/- 0.07 vs. 0.29 +/- 0.05, p < .05) and higher cardiac index (4.8 +/- 0.4 vs. 3.4 +/- 0.2 L.min-1.m-2, p < .05).
Zoniporide ameliorated myocardial injury during resuscitation from ventricular fibrillation through beneficial effects on energy metabolism without effects on coronary vascular resistance and coronary blood flow.
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ABSTRACT: Background: In addition to its role in the endogenous control of erythropoiesis, recombinant human erythropoietin (rh-EPO) has been shown to exert tissue protective properties in various experimental models. However, its role in the cardiac arrest (CA) setting has not yet been adequately investigated. Aim: The aim of this study is to examine the effect of rh-EPO in a pig model of ventricular fibrillation (VF)-induced CA. Methods: Ventricular fibrillation was electrically induced in 20 piglets and maintained untreated for 8 minutes before attempting resuscitation. Animals were randomized to receive rh-EPO (5000 IU/kg, erythropoietin [EPO] group, n = 10) immediately before the initiation of chest compressions or to receive 0.9% Sodium chloride solution instead (control group, n = 10). Results: Compared with the control, the EPO group had higher rates of return of spontaneous circulation (ROSC) (100% vs 60%, P = .011) and higher 48-hour survival (100% vs 40%, P = .001). Diastolic aortic pressure and coronary perfusion pressure during cardiopulmonary resuscitation were significantly higher in the EPO group compared with the control group. Erythropoietin-treated animals required fewer number of shocks in comparison with animals that received normal saline (P=.04). Furthermore, the neurologic alertness score was higher in the EPO group compared with that of the control group at 24 (P = .004) and 48 hours (P = .021). Conclusion: Administration of rh-EPO in a pig model of VF-induced CA just before reperfusion facilitates ROSC and improves survival rates as well as hemodynamic variables.American Journal of Emergency Medicine 04/2014; 32(8). DOI:10.1016/j.ajem.2014.04.036 · 1.15 Impact Factor
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ABSTRACT: IntroductionRecent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion (I/R) injury. The aim of the study was to determine if sildenafil will reduce the severity of post-resuscitation myocardial dysfunction and lead to cardioprotection through the beneficial effects on energy metabolism by obtaining metabolic evidence from microdialysis.Methods Twenty-four male pigets were randomly divided into three groups, sildenafil (n =8), saline (SA; n =8); and sham operation (SHAM; 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 min of untreated VF, the sidenafil group exhibited higher glucose and pyruvate concentrations of ISF and lower lactate and glutamate levels in comparison with the SA group, and reached statistical significance (P <0.05, respectively). Advanced cardiac life support was delivered to both groups, where 24-hour survival rate expressed a promising trend in the sildenafil group (7/8 versus 3/8 survivors, P <0.05). Compared with the SA group, the sildenafil group had a better outcome in hemodynamic and oxygen metabolism parameters (P <0.05, respectively). 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, P =0.02, respectively). Furthermore, after 24 hours of ROSC, the sildenafil group presented marked elevations of the activities of left ventricle Na+-K+-ATPase and Ca2+-ATPase than in the SA group (P =0.03, P =0.04, respectively).Conclusions Sildenafil could reduce the severity of post-resuscitation myocardial dysfunction and had better clearance of metabolic waste in the ISF. This work might provide insights into the development of a novel strategy to treat post-resuscitation myocardial dysfunction.Critical care (London, England) 12/2014; 18(6):641. DOI:10.1186/s13054-014-0641-7
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ABSTRACT: Background: Metabolic acidosis is associated with impaired cellular function. This has been attributed to the accompanying reduction in intracellular and interstitial pH of the myocardium. Recent studies suggest that activation of the cellular Na(+)-H(+) exchanger NHE1 might contribute to myocardial dysfunction. This review examines the experimental evidence which supports the role of NHE1 in the genesis of acidosis-induced cellular dysfunction, the benefits of its inhibition, and the type of acidosis that might benefit from therapy. Summary: Information was obtained by searching MEDLINE for articles published between 1969 and 2013 using the terms: NHE1, metabolic acidosis, lactic acidosis, ischemia-reperfusion, shock, resuscitation, high anion gap acidosis, and non-gap acidosis. Each article was also reviewed for additional suitable references. Nineteen manuscripts published between 2002 and 2013 assessed the impact of inhibition of NHE1 on cellular function. They revealed that NHE1 is activated with metabolic acidosis associated with hypoxia, hypoperfusion, hemorrhagic shock, and sepsis. This was associated with a rise in cellular sodium and calcium and cardiac dysfunction including reduced contractility and a predisposition to cardiac arrhythmias. Inhibition of NHE1 with specific inhibitors improved cardiac function, reduced blood and tissue levels of proinflammatory cytokines, and decreased mortality. Key Message: These results suggest that use of inhibitors of NHE1 might be worthwhile in the treatment of some types of acute metabolic acidosis, specifically the lactic acidosis associated with hypoxia, hemorrhagic shock, and cardiac arrest. Its potential role in the treatment of other forms of acute metabolic acidosis remains to be determined. © 2014 S. Karger AG, Basel.American Journal of Nephrology 07/2014; 40(1):36-42. DOI:10.1159/000364783 · 2.65 Impact Factor