Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, China.
J Appl Physiol (1985). 2013 Jan 15;114(2):238-44. doi: 10.1152/japplphysiol.00994.2012. Epub 2012 Nov 8.
Impairment of pulmonary endothelium function in the pulmonary artery is a direct result of chronic hypoxia. This study is to investigate the vasculoprotective effects of U50,488H (a selective κ-opioid receptor agonist) and its underlying mechanism in hypoxia-induced pulmonary artery endothelial functional injury. Chronic hypoxia was simulated by exposing the rats to 10% oxygen for 2 wk. After hypoxia, right ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI) were measured. The pulmonary vascular dysfunction, effect of nitric oxide synthase inhibitor (l-NAME) on the relaxation of U50,488H, and level of nitric oxide (NO) were determined. In vitro, the signaling pathway involved in the anti-apoptotic effect of U50,488H was investigated. Cultured endothelial cells were subjected to simulated hypoxia, and cell apoptosis was determined by TUNEL staining. U50,488H (1.25 mg/kg) significantly reduced RVP and RVHI in hypoxia. U50,488H markedly improved both pulmonary endothelial function (maximal vasorelaxation in response to ACh: 74.9 ± 1.8%, n = 6, P <0.01 vs. hypoxia for 2 wk group) and increased total NO production (1.65 fold). U50,488H relaxed the pulmonary artery rings of the hypoxic rats. This effect was partly abolished by l-NAME. In cells, U50,488H both increased NO production and reduced hypoxia-induced apoptosis. Moreover, pretreatment with nor-binaltorphimine (nor-BNI, a selective κ-opioid receptor antagonist), PI3K inhibitor, Akt inhibitor or l-NAME almost abolished anti-apoptotic effect exerted by U50,488H. U50,488H resulted in increases in Akt and eNOS phosphorylation. These results demonstrate that pretreatment with U50,488H attenuates hypoxia-induced pulmonary vascular endothelial dysfunction in an Akt-dependent and NO-mediated fashion.
肺动脉内皮功能障碍是慢性缺氧的直接结果。本研究旨在探讨 U50,488H（一种选择性 κ-阿片受体激动剂）对缺氧诱导的肺动脉内皮功能损伤的血管保护作用及其机制。通过将大鼠暴露于 10%氧气中 2 周来模拟慢性缺氧。缺氧后，测量右心室压（RVP）和右心室肥厚指数（RVHI）。测定肺血管功能障碍、一氧化氮合酶抑制剂（l-NAME）对 U50,488H 舒张的影响以及一氧化氮（NO）水平。在体外，研究了 U50,488H 抗凋亡作用的信号通路。将培养的内皮细胞置于模拟缺氧环境中，通过 TUNEL 染色测定细胞凋亡。U50,488H（1.25mg/kg）显著降低了缺氧大鼠的 RVP 和 RVHI。U50,488H 显著改善了肺内皮功能（对 ACh 的最大血管舒张反应：74.9±1.8%，n=6，与缺氧 2 周组相比，P<0.01）和增加总 NO 产生（1.65 倍）。U50,488H 舒张缺氧大鼠的肺动脉环。该作用部分被 l-NAME 阻断。在细胞中，U50,488H 增加了 NO 的产生并减少了缺氧诱导的凋亡。此外，用 nor-binaltorphimine（nor-BNI，一种选择性 κ-阿片受体拮抗剂）、PI3K 抑制剂、Akt 抑制剂或 l-NAME 预处理几乎消除了 U50,488H 发挥的抗凋亡作用。U50,488H 导致 Akt 和 eNOS 磷酸化增加。这些结果表明，U50,488H 的预处理以 Akt 依赖性和 NO 介导的方式减轻缺氧诱导的肺血管内皮功能障碍。
