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

  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.