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李晨, 李鑫, 刘春蕾, 杨明会. 马西替坦联合维利西呱治疗缺氧性肺高压大鼠的作用机制[J]. 解放军医学院学报, 2021, 42(10): 1058-1063. DOI: 10.3969/j.issn.2095-5227.2021.10.011
引用本文: 李晨, 李鑫, 刘春蕾, 杨明会. 马西替坦联合维利西呱治疗缺氧性肺高压大鼠的作用机制[J]. 解放军医学院学报, 2021, 42(10): 1058-1063. DOI: 10.3969/j.issn.2095-5227.2021.10.011
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LI Chen, LI Xin, LIU Chunlei, YANG Minghui. Mechanisms of combination of macitentan and vericiguat in the treatment of hypoxic pulmonary hypertension rats[J]. ACADEMIC JOURNAL OF CHINESE PLA MEDICAL SCHOOL, 2021, 42(10): 1058-1063. DOI: 10.3969/j.issn.2095-5227.2021.10.011
Citation: LI Chen, LI Xin, LIU Chunlei, YANG Minghui. Mechanisms of combination of macitentan and vericiguat in the treatment of hypoxic pulmonary hypertension rats[J]. ACADEMIC JOURNAL OF CHINESE PLA MEDICAL SCHOOL, 2021, 42(10): 1058-1063. DOI: 10.3969/j.issn.2095-5227.2021.10.011
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马西替坦联合维利西呱治疗缺氧性肺高压大鼠的作用机制

Mechanisms of combination of macitentan and vericiguat in the treatment of hypoxic pulmonary hypertension rats

    摘要
  • 摘要:
      背景   缺氧性肺高压是一种由慢性缺氧引起的以平均肺动脉压增高为特征的慢性进展性疾病，限制右心室功能，具有严重危害。
      目的   探讨马西替坦(Macitentan)联合维利西呱(Vericiguat)治疗缺氧性肺高压大鼠的协同作用及机制。
      方法   将60只雄性SD大鼠随机分为5组：空白组、模型组、Macitentan组(Macitentan 10 mg/kg)、Vericiguat组(Vericiguat 10 mg/kg)、Maci&Veri组(Macitentan 10 mg/kg+Vericiguat 10 mg/kg)，每组12只。空白组在非氧舱中饲养，其余各组大鼠在相同环境下10%氧浓度低氧舱中饲养2周，模拟5500 m高原环境。造模完成后，各组每日灌胃相应药物，空白组和模型组灌胃等量0.9%氯化钠注射液，连续2周。在第4周比较大鼠平均肺动脉压、右心肥厚比、右心功能指标，观察右心室、肺小血管病理学改变，检测肺动脉高压相关因子如超氧化物歧化酶(superoxide dismutase，SOD)、重组人骨形态发生蛋白2(bone morphogenetic protein 2，BMP2)、Rho卷曲蛋白激酶2(Rho-associated coiled-coil containing protein kinase 2，ROCK2)、过氧化物酶体增殖剂激活受体α(peroxisome proliferator activated receptor alpha，PPAR-α)、诱导型一氧化氮合酶(inducible nitric oxide synthase，iNOS)等蛋白的表达。
      结果  与空白组比较，模型组平均肺动脉压力(mean pulmonary artery pressure，mPAP)、右心室肥厚指数(right ventricular hypertrophy index，RVHI)显著升高，右心室射血分数(right ventricular ejection fraction，RVEF)、右心室缩短率(right ventricular fractional shortening，RVFS)、肺血流加速时间/肺射血时间(pulmonary blood flow acceleration time/pulmonary ejection time，PAT/PET)显著降低(P均＜0.01)；肺小血管壁(WT%)增厚(P＜0.05)，SOD、BMP2、PPAR-α表达降低(P＜0.05)，iNOS、ROCK2表达升高(P＜0.05)；与模型组比较，联合用药组mPAP、RVHI显著降低，RVEF、RVFS、PAT/PET显著升高(P均＜0.01)，结果优于马西替坦和维利西呱单独给药组(P＜0.05)；WT%降低(P＜0.01)，明显低于马西替坦和维利西呱单独给药组(P＜0.05)；SOD、BMP2、iNOS、PPAR-α表达升高(P＜0.05)，ROCK2表达降低(P＜0.05)，且BMP2表达高于马西替坦和维利西呱单独给药组(P＜0.05)。
      结论  马西替坦-维利西呱联合用药对缺氧性肺高压大鼠具有协同保护作用，可降低肺高压、提高心功能、改善肺血管重构和心肌损伤，并改变肺高压相关因子的表达。

     

    Abstract:
      Background   Hypoxic pulmonary hypertension (HPH) is a chronic progressive disease that is caused by chronic hypoxia and is characterized by increased mean pulmonary artery pressure, it limits the function of right ventricle and has serious damage.
      Objective   To investigate the effects and mechanisms of combination of Macitentan and Vericiguat in the treatment of hypoxic pulmonary hypertension rats.
      Methods   A total of 60 male rats were randomly divided into blank control group, vehicle group, Macitentan group (Macitentan 10 mg/kg), Vericiguat group (Vericiguat 10 mg/kg) and Macitentan-Vericiguat group (Macitentan 10 mg/kg+ Vericiguat 10 mg/kg). The rats, except those in the blank control group were housed in a hypoxia chamber with 10% oxygen concentration for 2 weeks, simulating a 5500-meter plateau environment. Then each group was given corresponding drugs every day, and the blank control and vehicle group were given same amount of 0.9% NaCl solution for 2 weeks. In the 4th week, the mean pulmonary artery pressure, right heart hypertrophy ratio, and right heart function indexes of rats were compared, and the pathomorphological changes of the right ventricle and pulmonary small vessels were observed. The expression of pulmonary hypertension-related factors such as SOD, BMP2, ROCK2, PPAR-α, iNOS, were detected.
      Results   Compared with the blank control group, the mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index (RVHI), right ventricular ejection fraction (RVEF), right ventricular fractional shortening (RVFS), and pulmonary blood flow acceleration time/pulmonary ejection time (PAT/PET) significantly reduced (all P＜0.01); and pulmonary small blood vessel wall (WT%) thickened (P＜0.05), the expression of SOD, BMP2, PPAR-α decreased (P＜0.05), iNOS, ROCK2 expression increased (P＜0.05). Compared with the vehicle group, the mPAP and RVHI in the combination of Macitentan and Vericiguat group decreased, while RVEF, RVFS, and PAT/PET increased (P＜0.01), the results were better than those of Macitentan or Vericiguat alone (P＜0.05); WT% decreased (P＜0.01), and was significantly lower than that of Macitentan or Vericiguat alone (P<0.05); SOD, BMP2, iNOS, PPAR-α expression increased (P＜0.05), ROCK2 expression decreased (P＜0.05), and the expression of BMP2 was significantly higher than that of Macitentan or Vericiguat alone (P＜0.05).
      Conclusion   The combination of Macitentan and Vericiguat has a synergistic protective effect on hypoxic pulmonary hypertension rats, which can reduce pulmonary hypertension, improve heart function, ameliorate pulmonary vascular remodeling and myocardial injury, and change the expression of pulmonary hypertension-related factors.

     

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