Dapagliflozin, sildenafil and their combination in monocrotaline-induced pulmonary arterial hypertension

作者：Yi Tang, Siyuan Tan, Minqi Li, Yijin Tang, Xiaoping Xu, Qinghai Zhang, Qinghua Fu, Mingxiang Tang, Jin He, Yi Zhang, Zhaofen Zheng, Jianqiang Peng, Tengteng Zhu, Wenlin Xie · 发表于：BMC Pulmonary Medicine · 年份：2022 · DOI：10.1186/s12890-022-01939-7 · 被引用次数：36 · 研究领域：Pulmonary Hypertension Research and Treatments、Phosphodiesterase function and regulation、Cardiovascular Function and Risk Factors

BACKGROUND: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), can reduce cardiovascular events and mortality in patients with heart failure. A number of mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors. The purpose of this study was to determine whether dapagliflozin can improve pulmonary vascular remodelling and the efficacy of dapagliflozin as an add-on therapy to sildenafil in rats with pulmonary arterial hypertension (PAH). METHODS: A monocrotaline (MCT)-induced PAH rat model was used in our study. MCT-injected rats were randomly divided into four groups and treated for 3 weeks with daily per os treatment with vehicle, dapagliflozin (1 mg/kg/day), sildenafil (25 mg/kg/day), or a combination of dapagliflozin (1 mg/kg/day) and sildenafil (25 mg/kg/day). Haemodynamic measurements, histological analysis, enzyme-linked immunosorbent assay and western blotting analysis were employed to detect the changes in PAH rats after treatments. RESULTS: Dapagliflozin significantly attenuated MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in PAH rats. Dapagliflozin effectively decreased the thickening of pulmonary artery media and decreased the muscularization of pulmonary arterioles in PAH rats. Moreover, dapagliflozin attenuated nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in lung tissues and the levels of interleukin-1β (IL-1β...