Departemnt of Emergency, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China; Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
Departemnt of Emergency, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China; Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi Province, China; Department of Cardiology, Traditional Chinese Medicine Hospital of Shaanxi Province, Xi'an, Shaanxi Province, China.
Eur J Pharmacol. 2018 Aug 5;832:129-137. doi: 10.1016/j.ejphar.2018.05.025. Epub 2018 May 18.
The present study aimed to investigate the role of quaternary ammonium salt of U50,488H (Q-U50,488H) in hypoxic pulmonary hypertension (HPH) and underlying mechanisms involved. A HPH animal model was established in rats under hypoxia and the mean pulmonary arterial pressure (mPAP) and right ventricular pressure (RVP) were measured. Relaxation of the pulmonary artery in response to Q-U50,488H was determined. In addition, expression and activity of endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) with NO content, Akt expression, total antioxidant capacity (T-AOC), and gp91phox were evaluated. Cell viability was determined by the cell counting kit-8 (CCK-8) assay. We demonstrated that both the molecular weight and solubility of Q-U50,488H were higher than that of U50,488H. Q-U50,488H reduced mPAP and RVP and prevented the development of HPH. Moreover, Q-U50,488H relaxed the pulmonary arteries from both normal and HPH rats in a time-dependent manner. Under hypoxic conditions, Q-U50,488H significantly increased Akt phosphorylation, eNOS phosphorylation, NO content in serum, and T-AOC in pulmonary arteries of HPH rats. In addition, the activity of eNOS was elevated, but the activity of iNOS was reduced when Q-U50,488H was given under hypoxia. Q-U50,488H significantly counteracted the increase of gp91phox expression in pulmonary arteries under hypoxia. In addition, in vitro studies suggested that Q-U50,488H inhibited pulmonary artery smooth muscle cells (PASMCs) proliferation under hypoxic conditions and that the effects of Q-U50,488H were blocked by nor-binaltorphimine (nor-BNI). Thus, our results provided evidence that Q-U50,488H plays a protective role against HPH via κ-opioid receptor stimulation.
本研究旨在探讨 U50,488H 的季铵盐（Q-U50,488H）在低氧性肺动脉高压（HPH）中的作用及其相关机制。在缺氧条件下建立大鼠 HPH 动物模型，测量平均肺动脉压（mPAP）和右心室压（RVP）。测定 Q-U50,488H 对肺动脉的舒张作用。此外，还评估了内皮型一氧化氮合酶（eNOS）和诱导型一氧化氮合酶（iNOS）的表达和活性、NO 含量、Akt 表达、总抗氧化能力（T-AOC）和 gp91phox。通过细胞计数试剂盒-8（CCK-8）测定细胞活力。我们证明，Q-U50,488H 的分子量和溶解度均高于 U50,488H。Q-U50,488H 降低 mPAP 和 RVP，并预防 HPH 的发展。此外，Q-U50,488H 可时间依赖性舒张正常和 HPH 大鼠的肺动脉。在缺氧条件下，Q-U50,488H 显著增加 HPH 大鼠血清中 Akt 磷酸化、eNOS 磷酸化、NO 含量和 T-AOC。此外，缺氧时给予 Q-U50,488H 可提高 eNOS 活性，降低 iNOS 活性。Q-U50,488H 可显著对抗缺氧时肺动脉中 gp91phox 表达的增加。此外，体外研究表明，Q-U50,488H 可抑制缺氧条件下肺动脉平滑肌细胞（PASMCs）的增殖，且 Q-U50,488H 的作用可被诺布啡烷（nor-BNI）阻断。因此，我们的研究结果提供了证据，表明 Q-U50,488H 通过 κ-阿片受体刺激在 HPH 中发挥保护作用。
