尼可地尔对猪心脏骤停后心肌损伤的保护作用

发布时间：2018-12-31 20:37

【摘要】：背景:复苏技术的进步已使自主循环的恢复率显著提升,然而心脏骤停的发生率和死亡率依然很高。复苏后心功能障碍是心脏骤停复苏后72h内高死亡率的主要原因。虽然复苏后心功能障碍被认为是暂时性的,但它与心脏骤停后动脉血压降低和低心输出量相关,旨在改善复苏后心功能障碍的干预措施可使临床受益。尼可地尔作为一种ATP敏感钾通道开放剂,是临床上用于治疗冠状动脉疾病的标准用药。基础和临床研究证据均显示尼可地尔可改善心脏缺血后收缩功能障碍,使冠状动脉闭塞和再灌注后心肌梗死面积缩小,然而关于尼可地尔在心脏骤停复苏模型中的应用研究仍然很少。目的:本研究用4min室颤诱发猪心脏骤停模型,探讨尼可地尔对复苏后心肌损伤的保护作用。方法:20头长白猪随机分为假手术组(n=4)和复苏组(n=16)。复苏组在手术后给予电刺激诱导室颤,4min后行心肺复苏术。假手术组给予手术而不诱发室颤。复苏组16头长白猪复苏成功并随机分为盐水对照组(n=8)和尼可地尔组(n=8),尼可地尔组即刻经中央静脉注射尼可地尔(150μg/kg),随后以3μg/(kg·min)静滴至再灌注结束;盐水对照组给予同剂量生理盐水。实验过程中连续监测血流动力学参数:心率、平均动脉压、心输出量、dp/dtmax和-dp/dtmax。致颤前和自主循环恢复后5、30、180和360min采取血样以检测肌钙蛋白Ⅰ和乳酸水平。在致颤前和自主循环恢复后6h行心脏多普勒超声评估左室射血分数。在自主循环恢复后6h将动物实施安乐死并留取心肌组织,行普通病理学及透射电镜检查观察心肌组织学损伤,用TUNEL法检测凋亡心肌细胞。用ELISA方法检测心肌组织中ATP浓度,Western Blot方法检测心肌组织中Bax、caspase-3和Bcl-2的表达。结果:自主循环恢复后6h,与盐水对照组相比,除-dp/dtmax和心率外(P0.05),尼可地尔可显著改善血流动力学参数,差异有统计学意义(P0.05)。与假手术组相比,盐水对照组动物的肌钙蛋白Ⅰ和乳酸水平复苏成功后升高,尼可地尔组使其水平显著降低,差异有统计学意义(P0.05)。与假手术组相比,盐水对照组动物的ATP浓度显著降低,而尼可地尔组其降低程度显著缓解,差异有统计学意义(P0.05)。与盐水对照组相比,尼可地尔组复苏后心肌组织学损伤减轻,TUNEL阳性细胞数目减少,差异有统计学意义(P0.05),心肌Bax和caspase-3的表达减少,Bcl-2的表达增加,差异有统计学意义(P0.05)。结论:尼可地尔可改善复苏后心功能障碍和能量代谢、减轻心肌组织学损伤和抗凋亡,从而对心脏骤停后心肌损伤产生保护作用。
[Abstract]:Background: advances in resuscitation have significantly increased the recovery rate of autonomic circulation, but the incidence and mortality of cardiac arrest remain high. Cardiac dysfunction after resuscitation was the main cause of high mortality within 72 hours after cardiac arrest. Although cardiac dysfunction after resuscitation is considered to be temporary, it is associated with decreased arterial blood pressure and low cardiac output after cardiac arrest. Intervention aimed at improving cardiac dysfunction after resuscitation may benefit clinical practice. As a ATP sensitive potassium channel opener, nicorandil is a standard drug for the treatment of coronary artery disease. Both basic and clinical studies have shown that nicorandil can improve the systolic dysfunction of the heart after ischemia and reduce myocardial infarction size after coronary artery occlusion and reperfusion. However, there are few studies on the application of nicordil in cardiac arrest and resuscitation models. Aim: to investigate the protective effect of nicorandil on myocardial injury after resuscitation in porcine cardiac arrest model induced by 4min ventricular fibrillation. Methods: 20 Landrace pigs were randomly divided into two groups: sham operation group (n = 4) and resuscitation group (n = 16). In the resuscitation group, electrical stimulation was given to induce ventricular fibrillation and cardiopulmonary resuscitation was performed after 4min. The sham group was given surgery without inducing ventricular fibrillation. Sixteen Landrace pigs in the resuscitation group were successfully resuscitated and randomly divided into two groups: saline control group (n = 8) and nicorandil group (n = 8). Nicodil (150 渭 g/kg) was immediately injected via central vein in nicorandil group. Then 3 渭 g / (kg min) was given intravenously to the end of reperfusion. Saline control group was given the same dose of normal saline. Continuous monitoring of hemodynamic parameters during the experiment: heart rate, mean arterial pressure, cardiac output, dp/dtmax and-dp/dtmax. Blood samples were taken to detect troponin I and lactate levels before fibrillation and after recovery of autonomic circulation. Left ventricular ejection fraction (LVEF) was evaluated by echocardiography before fibrillation and 6 hours after spontaneous circulation recovery. Euthanasia was performed 6 hours after the recovery of autonomic circulation and myocardial tissue was taken. The histological damage of myocardium was observed by general pathology and transmission electron microscopy. Apoptotic cardiomyocytes were detected by TUNEL method. The expression of Bax,caspase-3 and Bcl-2 in myocardial tissue was detected by ELISA and, Western Blot. Results: compared with saline control group, nicorandil significantly improved hemodynamic parameters except-dp/dtmax and heart rate (P0.05) at 6 h after recovery of autonomic circulation (P0.05). Compared with the sham operation group, the level of troponin I and lactate in saline control group increased after successful resuscitation, but the level of nicorandil group decreased significantly (P0.05). Compared with the sham operation group, the concentration of ATP in the saline control group was significantly lower than that in the nicorandil group (P0.05). Compared with the saline control group, the myocardial tissue injury and the number of TUNEL positive cells decreased after resuscitation in the nicorandil group (P0.05). The expression of Bax and caspase-3 decreased and the expression of Bcl-2 increased in the myocardium of nicorandil group. The difference was statistically significant (P0.05). Conclusion: nicorandil can improve cardiac dysfunction and energy metabolism after resuscitation, alleviate myocardial tissue injury and anti-apoptosis, and thus protect myocardium from cardiac arrest.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R541.78

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