N‐Acetylcysteine potentiates the haemodynamic‐improving effect of sildenafil in a rabbit model of acute pulmonary thromboembolism via the p38 MAPK pathway

• Published in: Clinical and experimental pharmacology & physiology 2019-02, Vol.46 (2), p.163-172
• Main Authors: Zhang, Ruipeng, Wang, Yang, Pan, Longfei, Tian, Hongyan
• Format: Article
• Language: English
• Subjects: Acetylcysteine; Acetylcysteine - pharmacology; Acute Disease; acute pulmonary thromboembolism; Alveoli; Animals; Apoptosis; Apoptosis - drug effects; Bronchus; Cell Count; Chemokine CCL2 - metabolism; Disease Models, Animal; Drug Synergism; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - pathology; FOXO1 protein; Health risk assessment; Hemodynamics; Hemodynamics - drug effects; Lipid peroxidation; Lipid Peroxidation - drug effects; Lipids; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung - physiopathology; Lungs; Male; MAP kinase; MAP Kinase Signaling System - drug effects; Matrix metalloproteinase; Matrix Metalloproteinase 9 - metabolism; Metalloproteinase; Neutrophils - cytology; Neutrophils - drug effects; Nitric Oxide - metabolism; n‐acetylcysteine; Oxidative stress; Oxidative Stress - drug effects; p38 Mitogen-Activated Protein Kinases - metabolism; Peroxidation; Pulmonary arteries; Pulmonary artery; Pulmonary Embolism - drug therapy; Pulmonary Embolism - metabolism; Pulmonary Embolism - pathology; Pulmonary Embolism - physiopathology; Rabbits; Signal transduction; Sildenafil; Sildenafil Citrate - pharmacology; Sildenafil Citrate - therapeutic use; Thromboembolism
• ISSN: 0305-1870; 1440-1681
• DOI: 10.1111/1440-1681.13039

Summary The current study aimed to investigate the effects of sildenafil and N‐acetylcysteine (NAC) on the haemodynamics in a rabbit model of acute pulmonary thromboembolism (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 matrix metalloproteinase (MMP) activity in bronchoalveolar lavage (BLA). Pulmonary artery endothelial cells were isolated, and their apoptosis rates and MMP activity were assayed. N‐acetylcysteine potentiated the haemodynamic‐improving effect of sildenafil and significantly inhibited the oxidative stress response. N‐acetylcysteine 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.