Nitric oxide (NO), an important endogenous signaling molecule released from vascular endothelial cells and nerves, activates the enzyme soluble guanylate cyclase to catalyze the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP, in turn, activates protein kinase G to phosphorylate a range of effector proteins in smooth muscle cells that reduce intracellular Ca²⁺ levels to inhibit both contractility and proliferation. The enzyme phosphodiesterase type 5 (PDE5) curtails the actions of cGMP by hydrolyzing it into inactive 5’-GMP. Small molecule PDE5 inhibitors (PDE5is), such as sildenafil, prolong the availability of cGMP and therefore, enhance NO-mediated signaling. PDE5is are the first-line treatment for erectile dysfunction but are also now approved for the treatment of pulmonary arterial hypertension (PAH) in adults. Persistent pulmonary hypertension in neonates (PPHN) is currently treated with inhaled NO, but this is an expensive option and around 1/3 of newborns are unresponsive, resulting in the need for alternative approaches. Here the development, chemistry and pharmacology of PDE5is, the use of sildenafil for erectile dysfunction and PAH, are summarized and then current evidence for the utility of further repurposing of sildenafil, as a treatment for PPHN, is critically reviewed.

一氧化氮（NO）是从血管内皮细胞和神经释放的重要内源性信号分子，它激活可溶性鸟苷酸环化酶以催化三磷酸鸟苷产生环状鸟苷单磷酸酯（cGMP）。反过来，cGMP激活蛋白激酶G，使平滑肌细胞中的一系列效应蛋白磷酸化，从而减少细胞内Ca ²⁺抑制收缩力和增殖的水平。5型磷酸二酯酶（PDE5）通过将cGMP水解为无活性的5'-GMP来减少其作用。小分子PDE5抑制剂（PDE5is）（例如西地那非）可延长cGMP的可用性，因此可增强NO介导的信号传导。PDE5is是勃起功能障碍的一线治疗药物，但现在也被批准用于成人肺动脉高压（PAH）的治疗。新生儿持续性肺动脉高压（PPHN）目前采用吸入式NO进行治疗，但这是一种昂贵的选择，大约1/3的新生儿无反应，因此需要其他方法。PDE5的开发，化学和药理学是西地那非用于勃起功能障碍和PAH的用途，