艾司洛尔在心肺复苏中的作用及机制

Effects and mechanism of short acting β- adrenergic antagonist Esmolol in a porcine resuscitation model

目的探讨β1-肾上腺素能受体阻滞剂艾司洛尔在大约克猪室颤心脏停搏心肺复苏模型的作用以及潜在的机制。方法50只健康成年雄性大约克猪在室颤4min后根据药物干预随机分为假手术组（Sham组）、肾上腺素组（AD组）、肾上腺素和艾司洛尔联合用药组（AD＋ES组），监测复苏后72h心电图，比较各组的心率、血压、冠脉灌注压、自主循环恢复、心功能等指标。死亡动物迅速取材，应用实时荧光定量PCR技术、免疫印迹技术检测左室基底部外膜层心肌钙／钙调素依赖性蛋白激酶Ⅱδ（calcium／calmodulin dependent protein kinaseⅡδ，CaMKⅡδ）的mRNA转录水平和蛋白表达水平。结果两组均有一只动物未能成功复苏。在复苏过程中两组自主循环恢复率、冠脉灌注压的差异无统计学意义。与Sham组相比，AD组和AD＋ES组复苏后心功能下降，但自主循环恢复后2h，AD＋ES组射血分数和心输出量显著高于AD组，更接近于Sham组。AD＋ES组复苏后72h恶性心律失常的发生率少于AD组，短期生存率高于AD组，心肌CaMKⅡδmRNA的相对表达量显著低于AD组[（1．76±0．12）雠（1．22±0．10），t=15．07，P=0．0001]。两组复苏72h内心源性死亡动物心肌CaMKⅡδ的mRNA相对表达量〉非心源性死亡动物〉72h后存活动物。蛋白免疫印迹结果表明各组CaMKⅡδ蛋白表达水平的差异与mRNA表达水平的差异是一致的。结论肾上腺素和艾司洛尔联合应用改善心肺复苏后心功能，减少恶性心律失常的发生，提高复苏后72h生存率。下调CaMKⅡδ的mRNA和蛋白表达水平是艾司洛尔减少复苏后室性心律失常发生的潜在分子学基础机制。

Objective To investigate the effect and mechanism of short acting β1-adrenergie antogonist Esmolol in a porcine model of ventricular fibrillation cardiac arrest. Method Totally 50 male Yorkshire pigs weighing （20± 2.5） kg were investigated. Ventricular fibrillation was untreated for 4 minutes before the start of precordial compression, mechanical ventilation, and attempted defibrillation. Animals were randomized to received 20 μg/kg adrenalin （AD group） or 20 μg/kg adrenalin combined 0.5 mg/kg Esmolol （AD ＋ ES group）. Return of spontaneous circulation （ROSC）, coronary perfusion pressure （CPP）, homodynamic variables, cardiac function and ventricular arrhythmias were studied and compared between groups. Real time-PCR and Western blotting were performed to determine the relative messenger RNA and protein expression levels of calcium handling proteins-- Calcium/Calmodulin dependent protein kinase Ⅱδ （ CaMK Ⅱδ）. Results Except one pig, the other pigs successfully resuscitated. No significant differences in ROSC and CPP between two groups. The heart function of resuscitated animals was significantly reduced in two groups. However, relatively rapid recovery to baseline values, less ventricular arrhytlunia and higher 72-hour survival rate were observed in the group treated with adrenalin combined Esmolol. The relative mRNA expression levels of CaMK Ⅱδ significantly decreased in the group treated with adrenahn combined Esmolol compared with the group treated with adrenalin alone [ （1.76±0.12） vs （ 1.22±0.10）, t = 15.07, p = 0.0001]. Both in AD group and AD＋ ES group, the mRNA expression of CaMKⅡδ were high at the myocardium of cardiac death animals within post-resuscitation 72-hour, lower in noncardiac death pigs and lowest in survival pigs. The result of Western blotting was consistent with these discrepancies. Conclusions Adrenalin combined Esmolol improves post-resuscitation 72-hour survival. The less shock defibrillation and the less ventricular arrhythmia contributed to this difference effect. One of the most important electrophysiological mechanisms is down regulation of the expression of mRNA and protein of CaMK Ⅱδ given a short acting β1-antagonist Esmolol at the early stage of ventricular fibrillation cardiac arrest.