U50 488H预处理大鼠诱导的延迟性心脏保护效应及其机制

The delayed cardioprotection with U50 488H pretreatment in rat heart and underlying mechanism

目的 :trans- (± ) - 3,4 - dichloro- N- methyl- N - [2 - (1- pyrrolidinyl) cyclohexyl]- benzeneacetam ide (U 5 0 4 88H)是κ阿片受体的选择性激动剂。实验观察静脉注射 U 5 0 4 88H (10 mg/ kg) 2 4 h后对心脏的延迟性保护作用及其细胞内机制。方法 :1采用离体灌流的大鼠心脏模型 ,通过局部缺血 /再灌注 ,以心脏梗死面积作为心脏损伤的判定标准 ,观察 U 5 0 4 88H预处理 (U P)对心脏的延迟性保护作用。 2采用分离的大鼠心肌细胞模型 ,通过代谢抑制(metabolic inhibition,MI) ,观察 UP对心肌细胞内静息 Ca2 + 和电诱导 Ca2 + 瞬变的影响。结果 :1U P可显著降低心脏梗死面积 ;2 U P的大鼠心肌细胞在 MI时 ,心肌细胞内静息 Ca2 + 的升高程度较对照组显著降低 ;3U P的大鼠心肌细胞在 MI时 ,心肌细胞电诱导 Ca2 + 瞬变的降低程度较对照组显著减少。上述作用均可被 U P前 10 min腹腔注射κ阿片受体的选择性阻断剂 nor- binaltorphim ine (10 m g/ kg)阻断。结论 ::U 5 0 4 88H可通过刺激κ阿片受体产生延迟性的心脏保护作用 ,此作用与心肌细胞内的 Ca2 + 稳态的调节有关。

AIM: To determine whether U50 488H, a selective agonist of κ opioid receptor, induces delayed cardioprotection in perfused rat heart and underlying cellular mechanism. METHODS: U50 488H in 10 mg/kg was given intravenously to the rat. 24 h later, the rat was killed and the isolated heart was subjected to ischemia/reperfusion. Myocardial injury was determined by measuring the infarct size at the end of the reperfusion. In addition, the ventricular myocytes were isolated, and the resting intracellular Ca 2+ ([Ca 2+] i) and the electrically-induced [Ca 2+] i transient were also observed upon the metabolic inhibition. RESULTS:U50 488H pretreatment (UP) significantly reduced the infarct size, attenuated the elevation in resting [Ca 2+] i and reduction in electrically-induced [Ca 2+] i in cardiomyocytes subjected to metabolic inhibition. The effects of UP were abolished when the selective κ opioid receptor antagonist nor-binaltorphimine at 10 mg/kg was administered 10 min prior to the U50 488H administration. CONCLUSION: The results demonstrate that UP induces the delayed cardioprotection by stimulating cardiac κ opioid receptor, and that the prevention or attenuation of alterations in Ca 2+ homeostasis induced by ischemic insult is involved in the cardioprotective effect of UP.