Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
Instituto de Química, Universidade Federal Fluminense, Rio de Janeiro, Rio de Janeiro, Brazil.
PLoS One. 2018 Apr 20;13(4):e0195047. doi: 10.1371/journal.pone.0195047. eCollection 2018.
Pulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death. This work investigated the effectiveness of a combined therapy with PDE5 inhibitor (PDE5i) and a new adenosine A2A receptor (A2AR) agonist in mitigating monocrotaline (MCT) induced PH in rats.
An in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs). In the in vivo experiments, PH was induced in male Wistar rats by a single intraperitoneal injection of 60 mg/kg MCT. Rats were divided into the following groups: control (saline injection only), MCT + vehicle, MCT + sildenafil, MCT + LASSBio 1359 and MCT + combination of sildenafil and LASSBio 1359. Fourteen days after the MCT injection, rats were treated daily with oral administration of the regimen therapies or vehicle for 14 days. Cardiopulmonary system function and structure were evaluated by echocardiography. RV systolic pressure and PA endothelial function were measured.
Isobolographic analysis showed a synergistic interaction between sildenafil and LASSBio 1359 in rat PAs. Combined therapy with sildenafil and LASSBio 1359 but not monotreatment with low dosages of either sildenafil or LASSBio 1359 ameliorated all of PH related abnormalities in cardiopulmonary function and structure in MCT challenged rats.
The combination of sildenafil and LASSBio 1359 has a synergistic interaction, suggesting that combined use of these pharmacological targets may be an alternative to improve quality of life and outcomes for PH patients.
肺动脉高压（PH）的特征是肺血管阻力增加，导致右心室（RV）压力超负荷，从而导致右侧心力衰竭和死亡。本研究旨在探讨磷酸二酯酶 5 抑制剂（PDE5i）与新型腺苷 A2A 受体（A2AR）激动剂联合治疗对大鼠野百合碱（MCT）诱导的 PH 的疗效。
采用等辐射分析法研究西地那非和 LASSBio 1359 对大鼠肺动脉（PA）的可能协同舒张作用。在体内实验中，通过单次腹腔注射 60mg/kg MCT 诱导雄性 Wistar 大鼠 PH。将大鼠分为以下几组：对照组（仅注射生理盐水）、MCT+载体、MCT+西地那非、MCT+LASSBio 1359 和 MCT+西地那非和 LASSBio 1359 联合治疗组。MCT 注射后 14 天，大鼠每天给予口服治疗方案或载体治疗 14 天。通过超声心动图评估心肺系统功能和结构。测量 RV 收缩压和 PA 内皮功能。
等辐射分析显示，西地那非和 LASSBio 1359 在大鼠 PA 中具有协同相互作用。与单独使用低剂量西地那非或 LASSBio 1359 相比，联合使用西地那非和 LASSBio 1359 可改善 MCT 挑战大鼠心肺功能和结构相关的所有 PH 异常。
西地那非和 LASSBio 1359 的联合具有协同作用，提示联合使用这些药物靶点可能是改善 PH 患者生活质量和结局的一种替代方法。
