Dempsie Y, MacLean M R
Division of Neuroscience and Biomedical Systems, Institute of Biomedical Sciences, University of Glasgow, Scotland, UK.
Br J Pharmacol. 2008 Oct;155(4):455-62. doi: 10.1038/bjp.2008.241. Epub 2008 Jun 9.
Pulmonary arterial hypertension (PAH) is characterized by a sustained and progressive elevation in pulmonary arterial pressure and pulmonary vascular remodelling leading to right heart failure and death. Prognosis is poor and novel therapeutic approaches are needed. The serotonin hypothesis of PAH originated in the 1960s after an outbreak of the disease was reported among patients taking the anorexigenic drugs aminorex and fenfluramine. These are indirect serotonergic agonists and serotonin transporter substrates. Since then many advances have been made in our understanding of the role of serotonin in the pathobiology of PAH. The rate-limiting enzyme in the synthesis of serotonin is tryptophan hydroxylase (Tph). Serotonin is synthesized, through Tph1, in the endothelial cells of the pulmonary artery and can then act on underlying pulmonary arterial smooth muscle cells and pulmonary arterial fibroblasts in a paracrine fashion causing constriction and remodelling. These effects of serotonin can be mediated through both the serotonin transporter and serotonin receptors. This review will discuss our current understanding of 'the serotonin hypothesis' of PAH and highlight possible therapeutic targets within the serotonin system.
肺动脉高压（PAH）的特征是肺动脉压力持续且渐进性升高以及肺血管重塑，最终导致右心衰竭和死亡。其预后较差，需要新的治疗方法。PAH的5-羟色胺假说起源于20世纪60年代，当时有报道称服用食欲抑制剂氨基雷克斯和芬氟拉明的患者中爆发了这种疾病。这些药物是间接的5-羟色胺能激动剂和5-羟色胺转运体底物。从那时起，我们对5-羟色胺在PAH病理生物学中的作用的理解有了许多进展。5-羟色胺合成中的限速酶是色氨酸羟化酶（Tph）。5-羟色胺通过Tph1在肺动脉内皮细胞中合成，然后可以以旁分泌方式作用于下层的肺动脉平滑肌细胞和肺动脉成纤维细胞，导致收缩和重塑。5-羟色胺的这些作用可以通过5-羟色胺转运体和5-羟色胺受体介导。本综述将讨论我们目前对PAH“5-羟色胺假说”的理解，并强调5-羟色胺系统内可能的治疗靶点。
