Rondelet Benoit, Kerbaul François, Van Beneden Ronald, Motte Sophie, Fesler Pierre, Hubloue Ives, Remmelink Myriam, Brimioulle Serge, Salmon Isabelle, Ketelslegers Jean-Marie, Naeije Robert
Laboratory of Physiology, Faculty of Medicine, Free University Brussels, Belgium.
Circulation. 2004 Oct 12;110(15):2220-5. doi: 10.1161/01.CIR.0000143836.40431.F5. Epub 2004 Oct 4.
The phosphodiesterase type-5 (PDE-5) inhibitor sildenafil has been reported to improve pulmonary arterial hypertension (PAH), but the mechanisms that account for this effect are incompletely understood. Severe pulmonary hypertension has been characterized by defects in a signaling pathway involving angiopoietin-1 and the bone morphogenetic receptor-2 (BMPR-2). We investigated the effects of sildenafil on hemodynamics and signaling molecules in a piglet overcirculation-induced model of early PAH.
Thirty 3-week-old piglets were randomized to placebo or sildenafil therapy 0.75 mg/kg TID after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by pulmonary tissue sampling for morphometry, immunohistochemistry or radioimmunoassay, and real-time quantitative-polymerase chain reaction. Chronic systemic-to-pulmonary shunting increased pulmonary mRNA for angiopoietin-1, endothelin-1 (ET-1), angiotensin II, inducible nitric oxide synthase, vascular endothelial growth factor, and PDE-5. Pulmonary messenger RNA for BMPR-1A and BMPR-2 decreased. Pulmonary angiotensin II, ET-1, and vascular endothelial growth factor proteins increased. Pulmonary artery pressure increased from 20+/-2 to 33+/-1 mm Hg, and arteriolar medial thickness increased by 91%. The expressions of angiopoietin-1, ET-1, and angiotensin II were tightly correlated to pulmonary hypertension. Sildenafil prevented the increase in pulmonary artery pressure, limited the increase in medial thickness to 41%, and corrected associated biological perturbations except for the angiopoietin-1/BMPR-2 pathway, PDE-5, and angiotensin II.
Sildenafil partially prevents overcirculation-induced PAH and associated changes in signaling molecules. Angiotensin II, PDE-5, and angiopoietin-1/BMPR-2 signaling may play a dominant role in the early stages of the disease.
据报道，5型磷酸二酯酶（PDE - 5）抑制剂西地那非可改善肺动脉高压（PAH），但其作用机制尚不完全清楚。严重肺动脉高压的特征是涉及血管生成素 - 1和骨形态发生蛋白受体 - 2（BMPR - 2）的信号通路存在缺陷。我们在仔猪过度循环诱导的早期PAH模型中研究了西地那非对血流动力学和信号分子的影响。
30只3周龄仔猪在左锁骨下动脉与肺动脉主干吻合或假手术后，随机分为安慰剂组或西地那非治疗组（0.75 mg/kg，每日3次）。3个月后，对动物进行血流动力学评估，随后采集肺组织进行形态学测量、免疫组织化学或放射免疫分析以及实时定量聚合酶链反应。慢性体肺分流增加了血管生成素 - 1、内皮素 - 1（ET - 1）、血管紧张素II、诱导型一氧化氮合酶、血管内皮生长因子和PDE - 5的肺mRNA水平。BMPR - 1A和BMPR - 2的肺信使RNA水平降低。肺血管紧张素II、ET - 1和血管内皮生长因子蛋白增加。肺动脉压从20±2 mmHg升高至33±1 mmHg，小动脉中层厚度增加91%。血管生成素 - 1、ET - 1和血管紧张素II的表达与肺动脉高压密切相关。西地那非可预防肺动脉压升高，将中层厚度增加限制在41%，并纠正了除血管生成素 - 1/BMPR - 2途径、PDE - 5和血管紧张素II之外的相关生物学紊乱。
西地那非可部分预防过度循环诱导的PAH及信号分子的相关变化。血管紧张素II、PDE - 5和血管生成素 - 1/BMPR - 2信号通路可能在该疾病的早期阶段起主导作用。
