Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension
Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension
复制标题
DOI：
10.1183/09031936.00140309
复制
发表时间：
2010-10-01
影响因子：
24.3
通讯作者：
Schermuly, R. T.
中科院分区：
文献类型：
--
作者：
Dahal, B. K.;Kosanovic, D.;Schermuly, R. T.
越来越多的证据表明Rho激酶（ROCK）参与了肺动脉高压（PH）的发病机制。氮杂吲哚-1（azaindole-1）是一种新型的高选择性口服ROCK抑制剂，其治疗PH的疗效尚未研究。本研究旨在研究氮杂吲哚-1对1）急性缺氧性肺血管收缩（HPV），2）肺动脉平滑肌细胞（PASMC）增殖和3）PH动物模型的影响。通气和缓冲液灌注的鼠肺和体外原代大鼠PASMCs的增殖。在大鼠注射野百合碱（MCT）和小鼠缺氧暴露后21至35天口服氮杂吲哚-1。Azaindole-1（大鼠和小鼠每天分别为10和30 mg/kg体重）显著改善血液动力学和右心室肥大。此外，周围肺动脉的中壁厚度和肌化得到改善。Azaindole-1处理导致MCT注射大鼠肺血管中磷酸肌球蛋白磷酸酶靶亚基1和增殖细胞核抗原的免疫反应性降低，表明ROCK活性受损和增殖细胞减少。Azaindole-1在实验性PH中提供治疗益处，这可能归因于其有效的血管舒张和抗增殖作用。Azaindole-1可能为PH的治疗提供有用的方法。
An accumulating body of evidence incriminates Rho kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). The therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH.This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH.Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline (MCT) injection in rats and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg per kg body weight per day in rats and mice, respectively) significantly improved haemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularisation of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 and proliferating cell nuclear antigen in pulmonary vessels of MCT-injected rats, suggesting an impaired ROCK activity and reduced proliferating cells.Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.