Yamamura Aya
School of Pharmacy, Kinjo Gakuin University, Japan.
J Smooth Muscle Res. 2014;50:8-17. doi: 10.1540/jsmr.50.8.
Pulmonary arterial hypertension (PAH) is defined as an intractable disease characterized by a progressive elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP), leading to right heart failure and premature death. The five-year survival rate after diagnosis is approximately 57%. Although extensive research has identified some factors associated with the cause of PAH, the etiology and pathogenesis remain unclear. In addition to Ca(2+) channel blockers (nifedipine, diltiazem), three categories of drug have been developed for the treatment of PAH based on the pathological mechanisms: prostacyclin and its analogues (epoprostenol, treprostinil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan), and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil). However, screening of novel types of drug acting on the signal pathway associated with the pathological mechanism underlying PAH is ongoing. We recently found that the extracellular Ca(2+)-sensing receptor (CaSR), which belongs to family C of the G protein-coupled receptor (GPCR) superfamily, is upregulated in pulmonary arterial smooth muscle cells (PASMCs) from patients with idiopathic PAH (IPAH). The upregulated CaSR is necessary for the enhanced Ca(2+) signaling and the augmented cell proliferation in PASMCs from IPAH patients. Most importantly, blockage of CaSR with an antagonist, NPS2143, prevents the development of pulmonary hypertension and right ventricular hypertrophy in animal models of pulmonary hypertension. The use of calcilytics, antagonists of CaSR, may be a novel therapeutic approach for PAH patients.
肺动脉高压（PAH）被定义为一种难治性疾病，其特征是肺血管阻力（PVR）和肺动脉压（PAP）进行性升高，导致右心衰竭和过早死亡。诊断后的五年生存率约为57%。尽管广泛的研究已经确定了一些与PAH病因相关的因素，但其病因和发病机制仍不清楚。除了钙（Ca2+）通道阻滞剂（硝苯地平、地尔硫䓬）外，基于病理机制已开发出三类药物用于治疗PAH：前列环素及其类似物（依前列醇、曲前列尼尔、伊洛前列素）、内皮素受体拮抗剂（波生坦、安立生坦）和5型磷酸二酯酶抑制剂（西地那非、他达拉非）。然而，针对作用于PAH潜在病理机制相关信号通路的新型药物的筛选仍在进行中。我们最近发现，属于G蛋白偶联受体（GPCR）超家族C类的细胞外钙（Ca2+）敏感受体（CaSR）在特发性PAH（IPAH）患者的肺动脉平滑肌细胞（PASMCs）中上调。上调的CaSR对于IPAH患者PASMCs中增强的Ca2+信号传导和增加的细胞增殖是必需的。最重要的是，用拮抗剂NPS2143阻断CaSR可预防肺动脉高压动物模型中肺动脉高压和右心室肥大的发展。使用钙敏感受体拮抗剂（calcilytics）可能是PAH患者一种新的治疗方法。
