Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Department of Physiological Sciences, Federal Rural University of Rio de Janeiro, Seropedica, RJ, Brazil.
Cardiovasc Drugs Ther. 2021 Aug;35(4):719-732. doi: 10.1007/s10557-020-07115-5. Epub 2020 Nov 27.
In the present study, the therapeutic efficacy of a selective BK channel opener (compound X) in the treatment of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) was investigated.
PAH was induced in male Wistar rats by a single injection of MCT. After two weeks, the MCT-treated group was divided into two groups that were either treated with compound X or vehicle. Compound X was administered daily at 28 mg/kg. Electrocardiographic, echocardiographic, and haemodynamic analyses were performed; ex vivo evaluations of pulmonary artery reactivity, right ventricle (RV) and lung histology as well as expression levels of α and β myosin heavy chain, brain natriuretic peptide, and cytokines (TNFα and IL10) in heart tissue were performed.
Pulmonary artery rings of the PAH group showed a lower vasodilatation response to acetylcholine, suggesting endothelial dysfunction. Compound X promoted strong vasodilation in pulmonary artery rings of both control and MCT-induced PAH rats. The untreated hypertensive rats presented remodelling of pulmonary arterioles associated with increased resistance to pulmonary flow; increased systolic pressure, hypertrophy and fibrosis of the RV; prolongation of the QT and T-T intervals (evaluated during electrocardiogram); increased lung and liver weights; and autonomic imbalance with predominance of sympathetic activity. On the other hand, treatment with compound X reduced pulmonary vascular remodelling, pulmonary flow resistance and RV hypertrophy and afterload.
The use of a selective and potent opener to activate the BK channels promoted improvement of haemodynamic parameters and consequent prevention of RV maladaptive remodelling in rats with MCT-induced PAH.
在本研究中，研究了一种选择性 BK 通道 opener（化合物 X）在治疗野百合碱（MCT）诱导的肺动脉高压（PAH）中的治疗效果。
雄性 Wistar 大鼠单次注射 MCT 诱导 PAH。两周后，将 MCT 处理组分为两组，一组用化合物 X 治疗，一组用载体治疗。化合物 X 每日以 28mg/kg 给药。进行心电图、超声心动图和血流动力学分析；进行肺动脉反应性、右心室（RV）和肺组织学的离体评估以及心脏组织中α和β肌球蛋白重链、脑钠肽和细胞因子（TNFα 和 IL10）表达水平的检测。
PAH 组的肺动脉环对乙酰胆碱的血管舒张反应较低，提示内皮功能障碍。化合物 X 促进了对照组和 MCT 诱导的 PAH 大鼠的肺动脉环的强烈血管舒张。未经治疗的高血压大鼠表现出肺小动脉重塑，与肺血流阻力增加相关；右心室收缩压升高、肥大和纤维化；心电图期间 QT 和 T-T 间期延长；肺和肝重量增加；以及自主神经失衡，交感神经活动占优势。另一方面，用化合物 X 治疗可减少肺血管重塑、肺血流阻力和 RV 肥大和后负荷。
使用选择性和有效的 opener 激活 BK 通道可改善血流动力学参数，并预防 MCT 诱导的 PAH 大鼠 RV 适应性重塑。
