Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Br J Pharmacol. 2018 Oct;175(20):3976-3989. doi: 10.1111/bph.14472. Epub 2018 Sep 16.
Pulmonary arterial hypertension (PAH) is a life-threatening disease that leads to progressive pulmonary hypertension, right heart failure and death. Parenteral prostaglandins (PGs), including treprostinil, a prostacyclin analogue, represent the most effective medical treatment for severe PAH. We investigated the effect of treprostinil on established severe PAH and underlying mechanisms using the rat SU5416 (SU, a VEGF receptor-2 inhibitor)-chronic hypoxia (Hx) model of PAH.
Male Sprague Dawley rats were injected with SU (20 mg·kg , s.c.) followed by 3 weeks of Hx (10% O ) to induce severe PAH. Four weeks post-SU injection, baseline right ventricular (RV) systolic pressure (RVSP) was measured, and the rats were randomized to receive vehicle or treprostinil treatment (Trep-100: 100 ng·kg ·min or Trep-810: 810 ng·kg ·min ). Following 3 weeks of treatment, haemodynamic and echocardiographic assessments were performed, and tissue samples were collected for protein expression and histological analysis.
At week 7, no difference in RVSP or RV hypertrophy was observed between vehicle and Trep-100; however, Trep-810 significantly reduced RVSP and RV hypertrophy. Trep-810 treatment significantly improved cardiac structure and function. Further, a short-term infusion of treprostinil in rats with established PAH at 4 weeks post-SU produced an acute, dose-dependent reduction in RVSP consistent with a vasodilator effect. However, chronic Trep-810 treatment did not alter media wall thickness, degree of vascular occlusion or total vessel count in the lungs.
Treprostinil exerts therapeutic benefits in PAH through decreased vascular resistance and improved cardiac structure and function; however, treprostinil treatment does not have direct impact vascular remodelling.
肺动脉高压（PAH）是一种危及生命的疾病，可导致进行性肺动脉高压、右心衰竭和死亡。肠外前列腺素（PGs），包括前列环素类似物曲前列尼尔，是治疗严重 PAH 的最有效药物。我们使用 SU5416（SU，一种 VEGF 受体-2 抑制剂）-慢性低氧（Hx）PAH 模型研究了曲前列尼尔对已建立的严重 PAH 的影响及其潜在机制。
雄性 Sprague Dawley 大鼠皮下注射 SU（20mg·kg ），然后进行 3 周的 Hx（10% O ）以诱导严重 PAH。SU 注射后 4 周，测量右心室（RV）收缩压（RVSP），并将大鼠随机分为接受载体或曲前列尼尔治疗（Trep-100：100ng·kg ·min 或 Trep-810：810ng·kg ·min ）。治疗 3 周后，进行血流动力学和超声心动图评估，并收集组织样本进行蛋白表达和组织学分析。
在第 7 周时，载体和 Trep-100 之间的 RVSP 或 RV 肥大没有差异；然而，Trep-810 显著降低了 RVSP 和 RV 肥大。Trep-810 治疗显著改善了心脏结构和功能。此外，在 SU 注射后 4 周的已建立 PAH 大鼠中，短期输注曲前列尼尔可导致 RVSP 急性、剂量依赖性降低，这与血管舒张作用一致。然而，慢性 Trep-810 治疗并没有改变肺部的中膜壁厚度、血管闭塞程度或总血管计数。
曲前列尼尔通过降低血管阻力和改善心脏结构和功能在 PAH 中发挥治疗作用；然而，曲前列尼尔治疗对血管重塑没有直接影响。
