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首页> 外文期刊>Life sciences >U50,488H postconditioning reduces apoptosis after myocardial ischemia and reperfusion.
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U50,488H postconditioning reduces apoptosis after myocardial ischemia and reperfusion.

机译：U50,488H后处理可减少心肌缺血和再灌注后的细胞凋亡。

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AIMS: Evidence has indicated U50,488H, a selective kappa-opioid receptor (kappa-OR) agonist, administered before ischemia attenuates apoptosis and infarction during ischemia and reperfusion (I/R). However, it remains unclear whether U50,488H postconditioning reduces apoptosis during I/R. This study was designed, therefore, to test the hypothesis that U50,488H administered at the onset of reperfusion inhibits cardiomyocyte apoptosis and to investigate the underlying mechanisms. MAIN METHODS: Male Sprague-Dawley rats were subjected to myocardial ischemia and reperfusion(MI/R) and were randomized to receive either vehicle, U50,488H, U50,488H plus Nor-BNI, a selective kappa-OR antagonist, U50,488H plus wortmannin, a specific inhibitor of phosphoinositide 3'-kinase (PI3K), or U50,488H plus L-NAME, a nitric oxide synthase inhibitor (NOS inhibitor), immediately prior to reperfusion. In vitro study was performed on cultured neonatal cardiomyocytes subjected to simulated ischemia/reperfusion. KEY FINDINGS: Treatment with U50,488H resulted in increases in Akt and endothelial nitric oxide synthase (eNOS) phosphorylation with secondary NO production both in vivo and in vitro and these effect were completely blocked by wortmannin and specific Akt inhibitor(AI). L-NAME treatment had no effect on Akt and eNOS phosphorylation; but, significantly reduced NO production. Moreover, treatment with U50,488H markedly reduced myocardial apoptotic death. Treatment with wortmannin and specific Akt inhibitor abolished the anti-apoptotic effect of U50,488H. L-NAME also significantly attenuated the anti-apoptotic effect of U50,488H. SIGNIFICANCE: These results demonstrate that U50,488H administered immediately prior to reperfusion increases Akt phosphorylation through a PI3-kinase-dependent mechanism and reduces postischemic myocardial apoptosis. Phosphorylation of eNOS with secondary NO production contribute significantly to the anti-apoptotic effect of U50,488H postconditioning.
机译：目的：证据表明，U50,488H是一种选择性的κ阿片受体（kappa-OR）激动剂，在缺血之前减轻缺血和再灌注（I / R）期间的细胞凋亡和梗塞。但是，尚不清楚U50,488H后处理是否会降低I / R期间的凋亡。因此，本研究旨在测试以下假设：在再灌注开始时施用U50,488H会抑制心肌细胞凋亡，并研究其潜在机制。主要方法：雄性Sprague-Dawley大鼠经历心肌缺血和再灌注（MI / R），并随机接受媒介物U50,488H，U50,488H加上选择性Kappa-OR拮抗剂Nor-BNI，U50,488H再灌注前立即加磷酸肌醇3'-激酶（PI3K）的特异性抑制剂渥曼青霉素，或U50,488H加一氧化氮合酶抑制剂（NOS抑制剂）L-NAME。对经过模拟的局部缺血/再灌注的培养的新生儿心肌细胞进行了体外研究。主要发现：用U50,488H进行处理后，体内和体外的Akt和内皮型一氧化氮合酶（eNOS）磷酸化增加，并产生二次NO，而渥曼青霉素和特定的Akt抑制剂（AI）完全阻断了这些作用。 L-NAME处理对Akt和eNOS磷酸化没有影响;但是，大大减少了NO的产生。此外，用U50,488H治疗可显着减少心肌细胞凋亡死亡。用渥曼青霉素和特定的Akt抑制剂治疗消除了U50,488H的抗凋亡作用。 L-NAME还显着减弱了U50,488H的抗凋亡作用。意义：这些结果表明，在再灌注前立即施用U50,488H可通过PI3激酶依赖性机制增强Akt磷酸化，并减少缺血后心肌细胞凋亡。 eNOS的磷酸化和二次NO的产生显着促进了U50,488H后处理的抗凋亡作用。

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