Abstract
ObjectivesSarcoplasmic reticulum (SR) Ca2+-handling proteins play an important role in myocardial dysfunction after acute ischemia/reperfusion injury. We hypothesized that nitrite would improve postresuscitation myocardial dysfunction by increasing nitric oxide (NO) generation and that the mechanism of this protection is related to the modulation of SR Ca2+-handling proteins.MethodsWe conducted a randomized prospective animal study using male Sprague-Dawley rats. Cardiac arrest was induced by intravenous bolus of potassium chloride (40 µg/g). Nitrite (1.2 nmol/g) or placebo was administered when chest compression was started. No cardiac arrest was induced in the sham group. Hemodynamic parameters were monitored invasively for 90 minutes after the return of spontaneous circulation (ROSC). Echocardiogram was performed to evaluate cardiac function. Myocardial samples were harvested 5 minutes and 1 hour after ROSC.ResultsMyocardial function was significantly impaired in the nitrite and placebo groups after resuscitation, whereas cardiac function (i.e., ejection fraction and fractional shortening) was significantly greater in the nitrite group than in the placebo group. Nitrite administration increased the level of nitric oxide in the myocardium 5 min after resuscitation compared to the other two groups. The levels of phosphorylated phospholamban (PLB) were decreased after resuscitation, and nitrite increased the phosphorylation of phospholamban compared to the placebo. No significant differences were found in the expression of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and ryanodine receptors (RyRs).Conclusionspostresuscitation myocardial dysfunction is associated with the impairment of PLB phosphorylation. Nitrite administered during resuscitation improves postresuscitation myocardial dysfunction by preserving phosphorylated PLB protein during resuscitation.
Highlights
According to recent epidemiological studies, approximately 70% of cardiac arrest (CA) patients who had restoration of spontaneous circulation (ROSC) died before hospital discharge [1,2,3]
No significant difference in Coronary perfusion pressure (CPP) during chest compression was found between the nitrite group and the placebo group
Nitrite improved cardiac dysfunction after CA/cardiopulmonary resuscitation (CPR) At 90 min after ROSC, the heart rate and mean arterial pressure (MAP) in placebo and nitrite group showed no significant differences compared to sham group
Summary
According to recent epidemiological studies, approximately 70% of cardiac arrest (CA) patients who had restoration of spontaneous circulation (ROSC) died before hospital discharge [1,2,3]. Postresuscitation myocardial dysfunction is one of the major factors contributing to the high mortality after initial resuscitation [4]. Cardiopulmonary resuscitation (CPR) strategies are continually updated, the mechanism of postresuscitation myocardial dysfunction remains poorly understood, and the available data are very limited. Novel therapies that might improve postresuscitation myocardial dysfunction require further exploration. Cardiac sarcoplasmic reticulum (SR) plays a central role in excitation-contraction coupling and myocardial contractile dysfunction through its Ca2+-modulating function [5]. The Ca2+ modulation of SR is associated with Ca2+-handling proteins, including sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), phospholamban (PLB) and ryanodine receptors (RyRs). Previous studies demonstrated that the ischemia-reperfusion (I/R) process might induce down-regulation of the expression and function of the SR proteins, which are involved in myocardial dysfunction after I/R injury [6,7]. Impairment of SR Ca2+ handling was shown to be involved in the Ca2+ overload observed during I/R injury, which induces hypercontraction of myofibrils and further mitochondrial injury in a Ca2+-related manner [8,9]
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