--- - |2 Abstract The current study aimed to investigate the effects of sildenafil and N‐acetylcysteine (NAC) on the haemodynamics in a rabbit model of APT. We developed an APT model using healthy male China big‐ear rabbits (2.7±0.4 kg). The rabbits were divided into five groups subjected to various interventions. We recorded the haemodynamic parameters and assessed the oxidative stress and lipid peroxidation response in the groups. Additionally, we detected apoptosis‐associated molecules, FoxO1, Bad and Bcl‐2, in the lung tissue. Gelatine zymography was used to detect MMP activity in bronchoalveolar lavage (BLA). Pulmonary artery endothelial cells were isolated, and their apoptosis rates and MMP activity were assayed. NAC potentiated the haemodynamic‐improving effect of sildenafil and significantly inhibited the oxidative stress response. NAC combined with sildenafil decreased MMP‐2 and MMP‐9 activity and NO consumption and inhibited apoptosis of pulmonary arterial endothelial cells. Moreover, NAC combined with sildenafil inhibited the expression of MCP‐1 and p‐p38 MAPK. Thus, NAC potentiates the haemodynamic‐improving effect of sildenafil in a rabbit model of acute pulmonary thromboembolism via the MCP‐1 and p38 MAPK signalling pathway. This study may provide a promising treatment method for APT. This article is protected by copyright. All rights reserved. - Clinical and Experimental Pharmacology and Physiology, Volume 0, Issue ja, -Not available-.