胰岛素依赖型糖尿病大鼠心肌对缺血再灌注的耐受性  

Cardiac Performance During Ischemia/reperfusion Injury in Type 1 Diabetic Rats

作　　者：蒲红[1] 顾坚忠[2] 符杰[2] 倪雅凤[2] 陈红[3] 

机构地区：[1]解放军第85医院心内科 [2]中科院上海实验动物中心 [3]上海交通大学医学院药理学教研室,上海200025

出　　处：《中华高血压杂志》2007年第1期34-38,共5页Chinese Journal of Hypertension

基　　金：国家重点基础研究发展规划(973项目)(NoG2000056905)

摘　　要：目的研究胰岛素依赖型糖尿病大鼠心肌对缺血再灌注损伤的耐受性及其机制。方法健康雄性SD大鼠以链脲佐菌素一次性腹腔注射破坏胰岛β细胞,造成胰岛素缺乏及高血糖,对照组腹腔注射等容积溶剂。注射链脲佐菌素4周后取心脏进行体外灌注,心脏缺血30min后再灌注30min,记录心功能及心律失常变化。实验分为对照组、糖尿病组、糖尿病一氧化氮合酶(NOS)抑制剂组,热休克蛋白90(hsp90)抑制剂组。一氧化氮合酶及hsp90抑制剂于心脏平衡灌注时加入灌注液中实验全程连续灌注。收集冠脉流出液测定肌酸激酶(CK),实验结束时测定心肌一氧化氮代谢产物(NOx)、热休克蛋白70(hsp70)及hsp90。结果与正常大鼠相比,糖尿病大鼠心脏基础收缩功能减弱,但缺血再灌注后心脏收缩及舒张功能较对照组显著增强。糖尿病心脏再灌注时心律失常及冠脉流出液CK含量较对照组显著减少,心肌NOx含量及hsp90显著增高,hsp70无显著变化。Hsp90抑制剂完全逆转了糖尿病心肌对缺血再灌注的耐受性,一氧化氮合成酶抑制剂使再灌注早期心律失常增加但对心脏功能无显著影响。结论早期胰岛素依赖型糖尿病大鼠心脏对缺血再灌注损伤的耐受性增强,其机制可能与心肌hsp90与NO合成增加有关。Objective To investigate the tolerance of myocardium to ischemia/reperfusion injury in type 1 diabetic rats and its possible mechanism. Methods Hearts from 3 weeks streptozocin-induced diabetes rats were isolated and subjected to 30 min ischemia and 30 min reperfusion. Cardiac function and electrocardiogram were recorded. Coronary creatine kinase and myocardial nitric oxide metabolites （NOx） were measured. Myocardial content of heat shock protein 70 and 90 （hsp70 and hsp90） was determined with Western Blot. A hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin （17-AAG） or nitric oxide synthase （NOS） inhibitor N^ω-nitro-L-arginine methyl ester （L-NAME） was added into the perfusate to study the effects of hsp90 inhibition and hsp90-associated endothelial NOS on ischemic response. Results Baseline diabetic heart function was decreased as compared with normal hearts. To our surprise, systolic and diastolic function in diabetic hearts was recovered more rapidly and to a better level at the end of reperfusion after ischemia than the normal rats. Compared with normal hearts, diabetic hearts also showed less＂ severe reperfusion arrhythmias and myocardial creatine kinase leakage. Myocardial NOx and hsp90 contents were increased in diabetes with no significant change in hsp70. Cardioprotection in diabetes rats was abolished by heat shock protein antagonist 17-AAG manifested by increases in CK, decreases in dp/dt, increases in LVGDP, duration of ventricular tachycardia and fibrillation and decrase in coronary artery blood flow. Conclusion Increases in myocardial hsp90 and nitric oxide production was found in diabetic myocardium, which may contribute to thier increased tolerance to ischemia/reperfusion injury.

关 键 词：胰岛素依赖型糖尿病 心肌缺血/再灌注损伤 心律失常 心功能 热休克蛋白90 

分 类 号：R587.1[医药卫生—内分泌]