Section of Pulmonary, Critical Care, and Sleep, Baylor College of Medicine, Houston, Texas, USA ; Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA.
Lerner Research Institute and Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Pulm Circ. 2015 Mar;5(1):124-34. doi: 10.1086/679720.
Decreased synthesis of nitric oxide (NO) by NO synthases (NOS) is believed to play an important role in the pathogenesis of pulmonary arterial hypertension (PAH). Multiple factors may contribute to decreased NO bioavailability, including increased activity of arginase, the enzyme that converts arginine to ornithine and urea, which may compete with NOS for arginine; inadequate de novo arginine production from citrulline; and increased concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS. We hypothesized that PAH patients with the lowest arginine availability secondary to increased arginase activity and/or inadequate de novo arginine synthesis might have a slower rate of NO synthesis and greater pulmonary vascular resistance. Nine patients with group 1 PAH and 10 healthy controls were given primed, constant intravenous infusions of (15)N2-arginine, (13)C,(2)H4-citrulline, (15)N2-ornithine, and (13)C-urea in the postabsorptive state. The results showed that, compared with healthy controls, PAH patients had a tendency toward increased arginine clearance and ornithine flux but no difference in arginine and citrulline flux, de novo arginine synthesis, or NO synthesis. Arginine-to-ADMA ratio was increased in PAH patients. Two endotypes of patients with low and high arginase activity were identified; compared with the low-arginase group, the patients with high arginase had increased arginine flux, slower NO synthesis, and lower plasma concentrations of ADMA. These results demonstrate that increased breakdown of arginine by arginase occurs in PAH and affects NO synthesis. Furthermore, there is no compensatory increase in de novo arginine synthesis to overcome this increased utilization of arginine by arginase.
一氧化氮合酶（NOS）合成的一氧化氮减少被认为在肺动脉高压（PAH）的发病机制中起重要作用。多种因素可导致一氧化氮生物利用度降低，包括精氨酸酶活性增加，该酶将精氨酸转化为鸟氨酸和尿素，可能与 NOS 竞争精氨酸；瓜氨酸从头合成精氨酸不足；以及不对称二甲基精氨酸（ADMA）浓度增加，ADMA 是 NOS 的内源性抑制剂。我们假设由于精氨酸酶活性增加和/或从头合成精氨酸不足导致精氨酸可用性最低的 PAH 患者可能具有更慢的一氧化氮合成率和更大的肺血管阻力。9 名 1 型 PAH 患者和 10 名健康对照者在吸收后状态下接受（15）N2-精氨酸、（13）C，（2）H4-瓜氨酸、（15）N2-鸟氨酸和（13）C-尿素的预输注、恒速静脉输注。结果表明，与健康对照者相比，PAH 患者精氨酸清除率和鸟氨酸通量呈增加趋势，但精氨酸和瓜氨酸通量、从头合成精氨酸或一氧化氮合成无差异。PAH 患者的精氨酸/ADMA 比值增加。确定了低和高精氨酸酶活性患者的两种表型；与低精氨酸酶组相比，高精氨酸酶组的患者精氨酸通量增加，一氧化氮合成更慢，血浆 ADMA 浓度更低。这些结果表明，PAH 中精氨酸的分解增加由精氨酸酶引起，并影响一氧化氮合成。此外，没有代偿性增加精氨酸的从头合成来克服精氨酸酶对精氨酸的这种利用增加。
