Murray F, Maclean M R, Insel P A
Department of Pharmacology and Department of Medicine, BSB 3073, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093-0636, USA.
Handb Exp Pharmacol. 2011(204):279-305. doi: 10.1007/978-3-642-17969-3_12.
Pulmonary arterial hypertension (PAH) is characterized by increased mean pulmonary artery pressure (mPAP) due to vasoconstriction and structural changes in the small pulmonary arteries (PAs); proliferation of pulmonary artery smooth muscle cells (PASMCs) contributes to the remodeling. The abnormal pathophysiology in the pulmonary vasculature relates to decreased cyclic nucleotide levels in PASMCs. Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby PDE inhibitors are effective in vasodilating the PA and decreasing PASMC proliferation. Experimental studies support the use of PDE3, PDE5, and PDE1 inhibitors in PAH. PDE5 inhibitors such as sildenafil are clinically approved to treat different forms of PAH and lower mPAP, increase functional capacity, and decrease right ventricular hypertrophy, without decreasing systemic arterial pressure. New evidence suggests that the combination of PDE inhibitors with other therapies for PAH may be beneficial in treating the disease. Furthermore, inhibiting PDEs in the heart and the inflammatory cells that infiltrate the PA may offer new targets to reduce right ventricular hypertrophy and inhibit inflammation that is associated with and contributes to the development of PAH. This chapter summarizes the advances in the area and the future of PDEs in PAH.
肺动脉高压（PAH）的特征是由于小肺动脉（PA）的血管收缩和结构变化导致平均肺动脉压（mPAP）升高；肺动脉平滑肌细胞（PASMCs）的增殖导致了血管重塑。肺血管系统中的异常病理生理学与PASMCs中环状核苷酸水平降低有关。磷酸二酯酶（PDEs）催化cAMP和cGMP的水解，因此PDE抑制剂可有效扩张肺动脉并减少PASMCs增殖。实验研究支持在PAH中使用PDE3、PDE5和PDE1抑制剂。西地那非等PDE5抑制剂已获临床批准用于治疗不同类型的PAH，可降低mPAP、提高功能能力并减轻右心室肥厚，且不会降低体动脉压。新证据表明，PDE抑制剂与PAH的其他治疗方法联合使用可能对治疗该病有益。此外，抑制心脏和浸润肺动脉的炎症细胞中的PDEs可能为减轻右心室肥厚和抑制与PAH发生发展相关并起作用的炎症提供新靶点。本章总结了该领域的进展以及PDEs在PAH治疗中的未来发展。
