【作者】 李凌峰；

【导师】 陈良万； 陈道中；

【作者基本信息】 福建医科大学 ， 外科学， 2008， 硕士

【摘要】 目的心肌肥厚是心脏对机械负荷及神经体液因子改变的代偿反应,各种心脏病在其自然进展中或多或少都将出现不同程度的心肌肥厚。其对缺血再灌注损伤的敏感性较正常心肌明显增加;已证明口服噻唑烷二酮类药物具有抗心肌缺血再灌注损伤及延缓或减轻心肌肥厚的作用。本课题观察和评价在离体大鼠肥厚心脏缺血再灌注损伤急性期应用噻唑烷二酮类药物(罗格列酮)的保护作用,并探讨其中可能的机制。方法实验选用健康6～7周龄SD大鼠40只随机分为正常心肌组(Con-N组)、肥厚心肌对照组(Con-H组)、肥厚心肌罗格列酮灌注组(Ros-H组),腹腔注射罗格列酮预处理组(Ros-O组),每组10只。建立经典压力负荷性心肌肥厚模型,予Con-H组、Ros-H组及Ros-O组行腹主动脉缩窄术后饲养5周,Con-N组行假手术。取心前,Ros-O组腹腔注射罗格列酮钠(重庆太极集团药业有限公司)生理盐水溶液(4mg·kg-1·d-1)预处理共7天。采用离体鼠心顺行灌注左心做功模型,观察各组心功能指标(LVSP、LVEDP)及缺血前、再灌注15分钟、30分钟、60分钟的N0、ET值、各组心肌酶(LDH、CK)的释放量、测定心脏肥厚指数、观察组织形态学及超微结构变化、TUNEL法检测细胞凋亡情况、凋亡调节蛋白Bcl-2、Bax的表达检测。结果⒈各组大鼠均全部存活,切口无感染、渗血,笼养期间无死亡。⒉Con-H组、Ros-H组及Ros-O组心脏肥厚指数明显高于Con-N组(P<0.0l ),且前三组间无明显差异。⒊Ros-H组在再灌注15、30、60分钟时间点LVSP均明显高于Con-H组(P<0.05或P<0.O1 ) ,但低于Ros-O组(P<0.05);LVEDP则明显低于Con-H组(P<0.O5)。⒋在再灌注15分钟冠脉流出液NO含量:Con-H组< Ros-H组和Ros-O组(P<0.01);ET含量:Con-H组> Ros-H组和Ros-O组(P<0.01)。⒌在再灌注15分钟心肌酶(LDH、CK)释放量:Con-H组> Ros-H组和Ros-O组(P<0.01)。⒍心肌组织凋亡指数:Con-H组> Ros-H组和Ros-O组(P<0.01)。⒎超微结构显示心肌细胞线粒体损伤程度:Con-H组> Ros-H组和Ros-O组(P<0.01)。结论⒈肥厚心肌再灌注期间,加入罗格列酮可明显改善其血流动力学,减少再灌注时心肌酶(LDH、CK)释放,增加NO合成,减少ET的释放,减少鼠离体肥厚性心肌缺血再灌注损伤,对其具有一定的保护作用。⒉肥厚心肌再灌注期间,加入罗格列酮可调节Bcl-2、Bax,即增加Bcl-2表达,减少Bax表达(Bcl-2/Bax增高),减少细胞凋亡作用,可能是减轻肥厚心肌再灌注损伤的一个重要机制。更多还原

【Abstract】 【Background】Previous Studies have shown that hypertrophied myocardium has nonuniform electrophysiologic propertie and electrotonic interaction compared with normal myocardium. Hypertrophied hearts have been demonstrated to have an increased vulnerability to ischemia-reperfusion injury. But studies on the methods for protection of the hypertrophied myocardium are rare and controversial. This study was carried out to investigate the effect of rosiglitazone treatment on the isolated reperfused rat hearts made hypertrophy by aortic banding.【Methods】Sprague-Daw1ey rats (aged 6~7 weeks) were subjected either to constriction of the abdominal aorta just above the renal artery or to sham operation. The rats were studied at 6 weeks of age, the hearts were subjected to 2h of global ischemia followed by 1 hour of reperfusion,with the method of rosiglitazone treatment. Animals completing the experiment included the normal age-matched control group(Con-N group, n = 10) ,the untreated group (Con-H, n = 10), rosiglitazone treated group in extracorporeal circulation(Con-N group,n=10), and rosiglitazone pretreated group(Ros-O group, n=10, daily 4mg·kg-1, for 7 days). Recovery of cardiac function, cardiac metabolism and myocardial morphology were assessed.【Results】The left ventricular weight/body weight ratio in the hypertrophied hearts was heigher in the age-matched controls (P<0.01). LVSP measured at 15, 30,60 minutes of reperfusion in group of aortic-constricted rats that were treated or pretreat with rosiglitazone were significantly higher than that of the untreated group (P<0.0l) and LVEDP measured at the same different time points were lower (P<0.0l).Compared with the untreated group,the level of ET、CK、LDH were also reduced (p<0.05 or p<0.01) and the level of NO was significantly increased (p<0.01). Morphometric study of electronmicro graphs demonstrated that mitochondria swelling was distinctlyless in Rosiglitazone-treated than in untreated rats (p<0.01). TENUL test also showed the AI in the Rosiglitazone pretreatment group were lower (p<0.01).【Conclusions】Rosiglitazone treatment and pretreatment in hypertrophied hearts results in significantly improved postischemic recoveries of cardiac function and provides superior protectior of hypertrophied rat hearts. Rosiglitazone reduces or delays the damage to the hypertrophied myocardiac cells. Moreover its effects are maximal in protecting cells from apoptosis, thereby suggesting that mitigating apoptosis may play an important role in rosiglitazone treatment and pretreatment’s ability to protect ischemic hypertrophied myocardium.更多还原