Weissmann Norbert, Hackemack Sascha, Dahal Bhola Kumar, Pullamsetti Soni Savai, Savai Rajkumar, Mittal Manish, Fuchs Beate, Medebach Thomas, Dumitrascu Rio, Eickels Martin van, Ghofrani Hossein Ardeschir, Seeger Werner, Grimminger Friedrich, Schermuly Ralph Theo
Univ. of Giessen Lung Center Medical Clinic II/V, Klinikstr. 36, 35392 Giessen, Germany.
Am J Physiol Lung Cell Mol Physiol. 2009 Oct;297(4):L658-65. doi: 10.1152/ajplung.00189.2009. Epub 2009 Jul 17.
Severe pulmonary hypertension (PH) is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right heart hypertrophy. In mice with PH induced by chronic hypoxia, we examined the acute and chronic effects of the soluble guanylate cyclase (sGC) activator HMR1766 on hemodynamics and pulmonary vascular remodeling. In isolated perfused mouse lungs from control animals, HMR1766 dose-dependently inhibited the pressor response of acute hypoxia. This dose-response curve was shifted leftward when the effects of HMR1766 were investigated in isolated lungs from chronic hypoxic animals for 21 days at 10% oxygen. Mice exposed for 21 or 35 days to chronic hypoxia developed PH, right heart hypertrophy, and pulmonary vascular remodeling. Treatment with HMR1766 (10 mg x kg(-1) x day(-1)), after full establishment of PH from day 21 to day 35, significantly reduced PH, as measured continuously by telemetry. In addition, right ventricular (RV) hypertrophy and structural remodeling of the lung vasculature were reduced. Pharmacological activation of oxidized sGC partially reverses hemodynamic and structural changes in chronic hypoxia-induced experimental PH.
重度肺动脉高压（PH）是一种致残性疾病，死亡率高，其特征为肺血管重塑和右心室肥厚。在慢性低氧诱导的PH小鼠模型中，我们研究了可溶性鸟苷酸环化酶（sGC）激活剂HMR1766对血流动力学和肺血管重塑的急性和慢性影响。在来自对照动物的离体灌注小鼠肺中，HMR1766呈剂量依赖性抑制急性低氧的升压反应。当在10%氧气浓度下对慢性低氧动物的离体肺进行21天研究时，HMR1766的这种剂量反应曲线向左移动。暴露于慢性低氧21天或35天的小鼠出现了PH、右心室肥厚和肺血管重塑。在从第21天到第35天PH完全形成后，用HMR1766（10 mg·kg⁻¹·天⁻¹）治疗，通过遥测连续测量发现可显著降低PH。此外，右心室（RV）肥厚和肺血管结构重塑也有所减轻。氧化型sGC的药理学激活可部分逆转慢性低氧诱导的实验性PH中的血流动力学和结构变化。
