Tong Yi, Jiao Qian, Liu Yuanru, Lv Jiankun, Wang Rui, Zhu Lili
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Front Pharmacol. 2018 Sep 21;9:1032. doi: 10.3389/fphar.2018.01032. eCollection 2018.
Pulmonary arterial hypertension (PAH) is a progressive disease caused by increased pulmonary artery pressure and pulmonary vascular resistance, eventually leading to right heart failure until death. Soluble guanylate cyclase (sGC) has been regarded as an attractive drug target in treating PAH. In this study, we discovered that maprotiline, a tetracyclic antidepressant, bound to the full-length recombinant sGC with a high affinity ( = 0.307 μM). Further study demonstrated that maprotiline concentration-dependently inhibited the proliferation of hypoxia-induced human pulmonary artery smooth muscle cells. Moreover, in a monocrotaline (MCT) rat model of PAH, maprotiline (ip, 10 mg/kg once daily) reduced pulmonary hypertension, inhibited the development of right ventricular hypertrophy and pathological changes of the pulmonary vascular remodeling. Taken together, our studies showed that maprotiline may contribute to attenuate disease progression of pulmonary hypertension.
肺动脉高压（PAH）是一种由肺动脉压力和肺血管阻力增加引起的进行性疾病，最终导致右心衰竭直至死亡。可溶性鸟苷酸环化酶（sGC）被认为是治疗PAH的一个有吸引力的药物靶点。在本研究中，我们发现四环类抗抑郁药马普替林与全长重组sGC具有高亲和力结合（ = 0.307 μM）。进一步研究表明，马普替林浓度依赖性地抑制缺氧诱导的人肺动脉平滑肌细胞的增殖。此外，在PAH的野百合碱（MCT）大鼠模型中，马普替林（腹腔注射，10 mg/kg，每日一次）降低了肺动脉高压，抑制了右心室肥厚的发展和肺血管重塑的病理变化。综上所述，我们的研究表明马普替林可能有助于减轻肺动脉高压的疾病进展。
