Macitentan Attenuates Chronic Mountain Sickness in Rats by Regulating Arginine and Purine Metabolism

Chronic mountain sickness (CMS) is a high altitude complication with high rates of morbidity and mortality. CMS is characterized by high-altitude polycythemia (HAPC) and high-altitude pulmonary hypertension (HAPH). In this study, macitentan, a dual endothelin receptor antagonist, was used to treat CMS, and the induced metabolomics changes were studied. CMS was induced in rats in a hypobaric hypoxia chamber (simulating a 5500 m plateau) for 4 weeks. Macitentan was administered in the third and fourth weeks (30 mg·kg^-1·day^-1). At the end of the follow-up period, we performed echocardiography, measured hemodynamic parameters and hematocrit, and performed histological staining. Furthermore, ultraperformance liquid chromatography-mass spectrometry (UPLC-MS)-based metabolic analysis was applied to explore metabolic changes associated with hypobaric hypoxia, with or without macitentan. qRT-PCR and kits for the determination of xanthine oxidase (XO) activity were used for validation experiments. Macitentan was effective in attenuating CMS, including CMS-induced right ventricle hypertrophy, HAPC, and HAPH. The levels of 48 metabolites were significantly changed in the CMS model group compared to the control group. Of these changes, 21 were reversed by treatment with macitentan. Enrichment analysis revealed that the purine metabolism pathway, as well as the arginine/proline metabolism pathway, might be the key pathways adjusted by macitentan. Furthermore, we verified macitentan played a beneficial role by directly regulating the expression of arginine1 and arginine2 in the arginine/proline metabolic pathway, and the activity of xanthine oxidase in the purine metabolic pathway. In conclusion, this study demonstrated that macitentan significantly ameliorated CMS in rats, and the mechanism was attributed to the reversion of the disorder in purine and arginine/proline metabolism, via direct regulation of XO activity and arginine1/2 expression. These findings are expected to provide new insights into the therapeutics and mechanism of macitentan in CMS.