Ambrisentan reduces pulmonary arterial hypertension but does not stimulate alveolar and vascular development in neonatal rats with hyperoxic lung injury.
Ambrisentan reduces pulmonary arterial hypertension but does not stimulate alveolar and vascular development in neonatal rats with hyperoxic lung injury.
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安立生坦可降低肺动脉高压，但不会刺激患有高氧性肺损伤的新生大鼠的肺泡和血管发育。
DOI：
10.1152/ajplung.00073.2012
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Walther,FransJ
中科院分区：
文献类型：
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作者：
Wagenaar,GerryTM;Laghmani,ElHouari;deVisser,YvonneP;Sengers,RozemarijnMA;Steendijk,Paul;Baelde,HansJ;Walther,FransJ
Ambrisentan 是一种 A 型内皮素受体拮抗剂，通过阻断血管收缩剂内皮素-1 的副作用，特别是肺动脉高压 (PAH) 引起的右心室肥大 (RVH)，可能成为新生儿慢性肺病 (CLD) 的新型治疗药物。我们在 2 个模型中测定了安立生坦治疗（1–20 mg·kg−1·day−1）对 CLD 新生大鼠的心肺影响：早期治疗持续暴露于高氧环境 10 天，晚期治疗从第 6 天开始，幼鼠出生后暴露于高氧环境 9 天，然后在室内空气中进行 9 天的恢复期。研究的参数包括存活率、肺和心脏组织病理学、右心室功能、纤维蛋白沉积和肺部差异 mRNA 表达。在早期治疗模型中，我们研究了安立生坦治疗期间 Nω-硝基-l-精氨酸甲酯（l-NAME；25 mg·kg−1·day−1）抑制一氧化氮合酶（NOS）的作用。在早期治疗模型中，ambrisentan 通过减少肺纤维蛋白和 III 型胶原沉积、动脉内壁厚度和 RVH 来改善生存。这些更改不受l-NAME 管理的影响。安立生坦不会减少巨噬细胞和中性粒细胞的流入，也不会阻止不规则弹性蛋白表达的减少。在后期治疗模型中，安立生坦降低了 PAH、RVH 和右心室峰值压力，表明 RVH 在新生儿期是可逆的。安立生坦不影响肺泡化和血管化。总之，ambrisentan 通过 NOS 独立机制延长生存并减少肺损伤、PAH 和 RVH，但不影响 CLD 新生大鼠的炎症、肺泡和血管发育。
Ambrisentan, an endothelin receptor type A antagonist, may be a novel therapeutic agent in neonatal chronic lung disease (CLD) by blocking the adverse effects of the vasoconstrictor endothelin-1, especially pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We determined the cardiopulmonary effects of ambrisentan treatment (1–20 mg·kg−1·day−1) in neonatal rats with CLD in 2 models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting onday 6in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included survival, lung and heart histopathology, right ventricular function, fibrin deposition, and differential mRNA expression in the lungs. In the early treatment model, we investigated the role of nitric oxide synthase (NOS) inhibition withNω-nitro-l-arginine methyl ester (l-NAME; 25 mg·kg−1·day−1) during ambrisentan treatment. In the early treatment model, ambrisentan improved survival with reduced lung fibrin and collagen III deposition, arterial medial wall thickness, and RVH. These changes were not affected byl-NAME administration. Ambrisentan did not reduce the influx of macrophages and neutrophils or prevent reduced irregular elastin expression. In the late treatment model, ambrisentan diminished PAH, RVH, and right ventricular peak pressure, demonstrating that RVH is reversible in the neonatal period. Alveolarization and vascularization were not affected by ambrisentan. In conclusion, ambrisentan prolongs survival and reduces lung injury, PAH, and RVH via a NOS-independent mechanism but does not affect inflammation and alveolar and vascular development in neonatal rats with CLD.