Pulmonary arterial hypertension (PAH) is a chronic and progressive disorder characterized by vascular remodeling of the small pulmonary arteries, resulting in elevated pulmonary vascular resistance and ultimately, right ventricular failure. Expanded understanding of PAH pathophysiology as it pertains to the nitric oxide (NO), prostacyclin (prostaglandin I₂) (PGI₂) and endothelin-1 pathways has led to recent advancements in targeted drug development and substantial improvements in morbidity and mortality. There are currently several classes of drugs available to target these pathways including phosphodiesterase-5 inhibitors (PDE5i), soluble guanylate cyclase (sGC) stimulators, prostacyclin class agents and endothelin receptor antagonists (ERAs). Combination therapy in PAH, either upfront or sequentially, has become a widely adopted treatment strategy, allowing for simultaneous targeting of more than one of these signaling pathways implicated in disease progression. Much of the current treatment landscape has focused on initial combination therapy with ambrisentan and tadalafil, an ERA and PDE5I respectively, following results of the AMBITION study demonstrating combination to be superior to either agent alone as upfront therapy. Consequently, clinicians often consider combination therapy with other drugs and drug classes, as deemed clinically appropriate, for patients with PAH. An alternative regimen that targets the NO and PGI₂ pathways has been adopted by some clinicians as an effective and sometimes preferred therapeutic combination for PAH. Although there is a paucity of prospective data, preclinical data and results from secondary data analysis of clinical studies targeting these pathways may provide novel insights into this alternative combination as a reasonable, and sometimes preferred, alternative approach to combination therapy in PAH. This review of preclinical and clinical data will discuss the current understanding of combination therapy that simultaneously targets the NO and PGI₂ signaling pathways, highlighting the clinical advantages and theoretical biochemical interplay of these agents.

肺动脉高压 (PAH) 是一种慢性进行性疾病，其特征是小肺动脉的血管重塑，导致肺血管阻力升高，最终导致右心室衰竭。扩展对 PAH 病理生理学的理解，因为它涉及一氧化氮 (NO)、前列环素 (prostaglandin I ₂ ) (PGI ₂) 和 endothelin-1 通路导致了靶向药物开发的最新进展以及发病率和死亡率的显着改善。目前有几类药物可用于靶向这些途径，包括磷酸二酯酶 5 抑制剂 (PDE5i)、可溶性鸟苷酸环化酶 (sGC) 刺激剂、前列环素类药物和内皮素受体拮抗剂 (ERA)。PAH 的联合治疗，无论是前期还是顺序，已成为一种广泛采用的治疗策略，允许同时靶向多个与疾病进展有关的信号通路。目前的大部分治疗领域都集中在安立生坦和他达拉非的初始联合治疗，分别是 ERA 和 PDE5I，根据 AMBITION 研究的结果，表明联合用药优于单独使用任何一种药物作为前期治疗。因此，临床医生通常会考虑与其他药物和药物类别的联合治疗，因为临床上认为对 PAH 患者是合适的。针对 NO 和 PGI 的替代方案一些临床医生已采用_{2种途径作为 PAH 的有效且有时首选的治疗组合。}尽管缺乏前瞻性数据，但临床前数据和针对这些途径的临床研究的二级数据分析结果可能为这种替代组合提供新的见解，作为一种合理的，有时是首选的 PAH 联合治疗的替代方法。这篇对临床前和临床数据的回顾将讨论目前对同时靶向 NO 和 PGI ₂信号通路的联合治疗的理解，突出这些药物的临床优势和理论上的生化相互作用。