Bayer AG, DD-TRG-CV III, Building 500, 42096, Wuppertal, Germany.
University of Witten/Herdecke, Witten, Germany.
Eur J Appl Physiol. 2018 Jan;118(1):195-203. doi: 10.1007/s00421-017-3761-3. Epub 2017 Nov 20.
Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal. We developed a new canine PH model in which pulmonary vasodilators can be characterized in conscious dogs and lung selectivity can be assessed non-invasively.
Telemetry devices were implanted to measure relevant hemodynamic parameters in conscious dogs. A hypoxic chamber was constructed in which the animals were placed in a conscious state. By reducing the inspired oxygen fraction (FiO) to 10%, a hypoxic pulmonary vasoconstriction was induced leading to PH. The PDE-5 inhibitor sildenafil, the current standard of care was compared to atrial natriuretic peptide (ANP).
The new hypoxic chamber provided a stable hypoxic atmosphere during all experiments. The mean PAP under normoxic conditions was 15.8 ± 1.8 mmHg. Hypoxia caused a reliable increase in mean PAP (+ 12.2 ± 3.2 mmHg, p < 0.0001). Both, sildenafil (- 6.8 ± 4.4 mmHg) and ANP (- 6.4 ± 3.8 mmHg) significantly (p < 0.05) decreased PAP. Furthermore sildenafil and ANP showed similar effects on systemic hemodynamics. In subsequent studies, the in vitro effects and gene expression pattern of the two pathways were exemplified.
By combining the hypoxic environment with the telemetric approach, we could successfully establish a new acute PH model. Sildenafil and ANP demonstrated equal effects regarding pulmonary selectivity. This non-invasive model could help to rapidly screen pulmonary vasodilators with decreased animal burden.
在动物模型中测试研究药物是药物开发的关键步骤。目前的肺动脉高压（PH）模型存在局限性。最相关的结果参数，如肺动脉压（PAP），是通过侵入性测量的，这需要对动物进行麻醉。我们开发了一种新的犬 PH 模型，其中可以在清醒的狗中对肺血管扩张剂进行特征描述，并可以非侵入性地评估肺选择性。
植入遥测设备以测量清醒犬的相关血流动力学参数。构建了一个低氧室，动物在其中处于清醒状态。通过将吸入氧气分数（FiO）降低到 10%，诱导低氧性肺血管收缩，导致 PH。将 PDE-5 抑制剂西地那非（目前的标准治疗方法）与心房利钠肽（ANP）进行比较。
新的低氧室在所有实验中提供了稳定的低氧环境。在正常氧条件下，平均 PAP 为 15.8±1.8mmHg。低氧引起平均 PAP 的可靠增加（+12.2±3.2mmHg，p<0.0001）。西地那非（-6.8±4.4mmHg）和 ANP（-6.4±3.8mmHg）均显著（p<0.05）降低 PAP。此外，西地那非和 ANP 对全身血液动力学有相似的影响。在随后的研究中，举例说明了两种途径的体外作用和基因表达模式。
通过将低氧环境与遥测方法相结合，我们成功地建立了一种新的急性 PH 模型。西地那非和 ANP 在肺选择性方面表现出相同的效果。这种非侵入性模型可以帮助快速筛选肺血管扩张剂，减少动物负担。
