Novel Oral Prostacyclin Analog With Thromboxane Synthase Inhibitory Activity for Management of Pulmonary Arterial Hypertension

ulmonary arterial hypertension (PAH) is a disease characterized by extensive remodeling of the small pulmonary arteries, resulting in increased elevated pulmonary arterial pressure and right ventricular heart failure.PAH is fatal if not treated, with only 34% survival rate after 5 years. 1 Pathobiologically, PAH is the result of a combination of many factors.2 Simplistically, abnormal proliferation of endothelial cells is an important mechanism, which leads to increased arginase activity and downregulation of prostacyclin (PGI2) synthase in lung tissues, and subsequent reduction in the production of the vasodilators nitric oxide (NO) and PGI2.3-5 Endothelial hyperproliferation also increases the production of endothelin-1 (ET-1), one of the most potent vasoconstrictors.ET-1 overexpression in turns reduces the production of NO and PGI2.These changes are associated with many other interrelated pathological changes, including vasoconstriction, hyper-proliferation of vascular smooth muscle cells and fibroblasts, vascular wall hypertrophy, inflammation, platelet aggregation, and thrombosis, all contributing to the remodeling of the pulmonary vasculature in PAH (Figure ). Article p 2127Based on these key features, currently approved therapies for PAH include phosphodiesterase 5 inhibitors (PDE-5I), endothelin-receptor antagonists (ERA) and PGI2 derivatives (Figure).PDE-5Is prevent cyclic GMP breakdown and therefore enhances the vasodilatory effect of NO, ameliorating the effect of reduced NO production.ERAs prevent ET-1 interacting with its receptors, thereby alleviating the effects of excessive ET-1 in PAH patients.PGI2 derivatives increase the levels of PGI2, thereby alleviating the vasoconstriction caused by PThe opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society.