The phosphodiesterase-5 inhibitor vardenafil reduces oxidative stress while reversing pulmonary arterial hypertension
The phosphodiesterase-5 inhibitor vardenafil reduces oxidative stress while reversing pulmonary arterial hypertension
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磷酸二酯酶 5 抑制剂伐地那非可减少氧化应激，同时逆转肺动脉高压
DOI：
10.1093/cvr/cvt109
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发表时间：
2013-08-01
影响因子：
10.8
通讯作者：
Jing, Zhi-Cheng
中科院分区：
文献类型：
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作者：
Fan, You-Fei;Zhang, Rui;Jing, Zhi-Cheng
氧化应激与肺动脉高压（PAH）的病理学有关。以前，我们证明了伐地那非，一种磷酸二酯酶-5抑制剂，有潜力作为PAH的治疗，尽管其机制尚未确定。在此，我们的目的是确定PAH患者的氧化应激基线水平，并研究伐地那非在改善PAH的同时是否影响氧化应激水平。对患有野百合碱诱导的PAH的SpragueDawley大鼠口服伐地那非1 mg kg（1），每天（1），共21天（n 12）。PAH初治患者（n 15）接受伐地那非5 mg每日两次治疗3个月。测定大鼠和患者的血液动力学数据和硝酸盐/亚硝酸盐和氧化损伤产物的血浆水平。在大鼠肺组织中进行组织学、免疫组织化学和氧化/抗氧化酶表达评估。与基线（患者）或未治疗的对照组（大鼠）相比，伐地那非显着降低了肺血管阻力并增加了心输出量（CO）。在大鼠中，伐地那非抑制肺动脉平滑肌细胞的增殖和增强凋亡，减弱小肺动脉重构和右心室肥大。伐地那非显著降低大鼠和患者的氧化应激生物标志物水平，如8-异前列腺素-F2和3-硝基酪氨酸，并显著增加一氧化氮（NO）水平。此外，伐地那非显着增加内皮NO合成酶的表达和超氧化物歧化酶的活性，并下调烟酰胺腺嘌呤二核苷酸磷酸氧化酶在大鼠肺组织中的表达。伐地那非降低氧化应激在大鼠和人类，同时改善PAH，促进研究氧化应激途径作为PAH治疗的目标。
Oxidative stress is implicated in the pathology of pulmonary arterial hypertension (PAH). Previously, we demonstrated that vardenafil, a phosphodiesterase-5 inhibitor, has potential as therapy for PAH, although the mechanism remained uncharacterized. Here, we aimed to determine baseline levels of oxidative stress in PAH and investigate whether vardenafil affects oxidative stress levels while improving PAH.SpragueDawley rats with monocrotaline-induced PAH were administered oral vardenafil 1 mg kg(1)day(1) for 21 days (n 12). Treatment-naive patients (n 15) with PAH were treated with vardenafil 5 mg twice daily for 3 months. Haemodynamic data and plasma levels of nitrate/nitrite and products of oxidative damage were determined in rats and patients. Histopathology, immunohistochemistry, and assessments of oxidative/anti-oxidative enzyme expression were performed in rat lung tissue. Compared with baseline (patients) or untreated controls (rats), vardenafil significantly reduced pulmonary vascular resistance and increased cardiac output (CO). In rats, vardenafil suppressed proliferation and enhanced apoptosis of pulmonary artery smooth muscle cells, attenuating small pulmonary artery remodelling, and right ventricular hypertrophy. Vardenafil significantly reduced levels of oxidative stress biomarkers, such as 8-iso-prostaglandin-F2 and 3-nitrotyrosine, and significantly increased nitric oxide (NO) levels in rats and patients. Furthermore, vardenafil significantly increased endothelial NO synthase expression and superoxide dismutase activity, and down-regulated nicotinamide adenine dinucleotide phosphate oxidase expression in rat lung tissue.Vardenafil reduces oxidative stress in rats and humans while improving PAH, warranting investigation of oxidative stress pathways as targets for PAH therapy.