Ambalavanan N, Mariani G, Bulger A, Philips III J B
Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, AL 35233-7335, USA.
Biol Neonate. 1999 Nov;76(5):291-300. doi: 10.1159/000014171.
Nitric oxide (NO), which is known to inhibit systemic vascular smooth muscle cell proliferation, is used in the management of neonatal pulmonary hypertension. Our objectives were to determine: (1) if endogenous NO production by neonatal porcine pulmonary artery smooth muscle cells (PASMCs) varied with oxygen tension in vitro, and (2) the effect of exogenous NO and inducible NO synthase (iNOS) stimulators and inhibitors on PASMC proliferation and apoptosis. PASMCs were exposed to different conditions (varying PO(2), NO donors and scavengers, iNOS stimulators and inhibitors) and proliferation, apoptosis, and cyclic guanosine 5(')-monophosphate (cGMP) assessed. PASMCs proliferated best between 5 and 10% O(2) but cGMP levels were similar at all oxygen levels. NO donors (S-nitroso-N-acetyl-penicillamine, NOC-12, NOC-18) inhibited PASMC proliferation in a dose-dependent manner with associated cGMP increases, while NO scavengers (carboxy-PTIO), iNOS stimulators (interleukin-1beta, lipopolysaccharide), and iNOS inhibitors (aminoethylisothiourea) did not affect proliferation or cGMP. No changes in apoptosis were found at the concentrations of NO donors or iNOS stimulators used. These results suggest that while exogenous NO inhibits PASMC proliferation, endogenous NO may not regulate proliferation during changes in oxygen tension or cytokine levels. Endothelial derived and inhaled NO may attenuate smooth muscle hyperplasia and vascular remodeling. Inducible NOS in porcine PASMCs appears resistant to stimulation with interleukin-1beta or lipopolysaccharide. The mechanisms underlying hypoxia-mediated changes in PASMC proliferation require investigation.
一氧化氮（NO）可抑制全身血管平滑肌细胞增殖，已用于新生儿肺动脉高压的治疗。我们的目的是确定：（1）新生猪肺动脉平滑肌细胞（PASMCs）内源性NO生成是否随体外氧张力变化而变化；（2）外源性NO、诱导型NO合酶（iNOS）刺激剂和抑制剂对PASMC增殖和凋亡的影响。将PASMCs置于不同条件下（不同的PO₂、NO供体和清除剂、iNOS刺激剂和抑制剂），并评估其增殖、凋亡和环磷酸鸟苷（cGMP）水平。PASMCs在5%至10% O₂之间增殖最佳，但所有氧水平下的cGMP水平相似。NO供体（S-亚硝基-N-乙酰青霉胺、NOC-12、NOC-18）以剂量依赖性方式抑制PASMC增殖，并伴有cGMP增加，而NO清除剂（羧基-PTIO）、iNOS刺激剂（白细胞介素-1β、脂多糖）和iNOS抑制剂（氨基乙基异硫脲）不影响增殖或cGMP。在所使用的NO供体或iNOS刺激剂浓度下，未发现凋亡有变化。这些结果表明，虽然外源性NO抑制PASMC增殖，但内源性NO可能在氧张力或细胞因子水平变化期间不调节增殖。内皮衍生的和吸入的NO可能减轻平滑肌增生和血管重塑。猪PASMCs中的诱导型NOS似乎对白细胞介素-1β或脂多糖刺激有抗性。缺氧介导的PASMC增殖变化的潜在机制需要研究。
