Schermuly Ralph Theo, Kreisselmeier Klaus Peter, Ghofrani Hossein Ardeschir, Samidurai Arun, Pullamsetti Soni, Weissmann Norbert, Schudt Christian, Ermert Leander, Seeger Werner, Grimminger Friedrich
Department of Internal Medicine, Justus-Liebig-University Giessen, Germany.
Circ Res. 2004 Apr 30;94(8):1101-8. doi: 10.1161/01.RES.0000126050.41296.8E. Epub 2004 Mar 18.
Severe pulmonary hypertension is a disabling disease with high mortality. We investigated acute and chronic effects of iloprost, a long-acting prostacyclin analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days after administration of the alkaloid, right ventricular systolic pressure increased from 25.8+/-2.0 to 62.9+/-3.4 and 70.5+/-7.4 mm Hg, with concomitant decline in cardiac index, central venous oxygen saturation, and arterial oxygenation. Marked right heart hypertrophy was demonstrated by the strongly elevated ratio of right ventricle/left ventricle plus septum weight, and massive thickening of the precapillary artery smooth muscle layer was shown histologically. Western blot analysis demonstrated increased levels of matrix metalloproteinases (MMPs) -2 and -9 and increased gelatinolytic activities in isolated pulmonary arteries. In these animals, both intravenous iloprost and tolafentrine displayed characteristic features of pulmonary vasodilators. When chronically infused from days 14 to 28, both agents significantly attenuated all monocrotaline-induced hemodynamic and gas exchange abnormalities as well as right heart hypertrophy. Full normalization of all variables including right ventricle size was achieved on combined administration of both agents during this period. This was also true for MMP-2 and MMP-9 expression and activity. Moreover, when iloprost plus tolafentrine was used for late therapeutic intervention, with infusion from days 28 to 42 after full establishment of severe pulmonary hypertension and cor pulmonale, hemodynamic, gas exchange, and cardiac and pulmonary vascular remodeling changes were significantly reversed. We conclude that the combined administration of iloprost and a dual-selective phosphodiesterase 3/4 inhibitor prevents and reverses the development of pulmonary hypertension and cor pulmonale in response to monocrotaline in rats. This regimen may therefore offer a possible antiremodeling therapy in severe pulmonary hypertension.
重度肺动脉高压是一种致残性疾病，死亡率很高。我们研究了长效前列环素类似物伊洛前列素和双选择性磷酸二酯酶3/4抑制剂托拉芬群对大鼠野百合碱诱导的肺动脉高压的急性和慢性影响。给予生物碱28天和42天后，右心室收缩压从25.8±2.0毫米汞柱升至62.9±3.4毫米汞柱和70.5±7.4毫米汞柱，同时心脏指数、中心静脉血氧饱和度和动脉氧合下降。右心室/左心室加室间隔重量比值大幅升高，表明右心明显肥大，组织学显示肺前毛细血管动脉平滑肌层大量增厚。蛋白质印迹分析表明，分离的肺动脉中基质金属蛋白酶（MMP）-2和-9水平升高，明胶酶活性增强。在这些动物中，静脉注射伊洛前列素和托拉芬群均表现出肺血管扩张剂的特征。从第14天至28天进行慢性输注时，两种药物均显著减轻了野百合碱诱导的所有血流动力学和气体交换异常以及右心肥大。在此期间联合使用两种药物可使包括右心室大小在内的所有变量完全恢复正常。MMP-2和MMP-9的表达及活性也是如此。此外，当伊洛前列素加托拉芬群用于晚期治疗干预时，即在重度肺动脉高压和肺心病完全形成后的第28天至42天进行输注，血流动力学、气体交换以及心脏和肺血管重构变化均得到显著逆转。我们得出结论，伊洛前列素与双选择性磷酸二酯酶3/4抑制剂联合使用可预防和逆转大鼠因野百合碱所致的肺动脉高压和肺心病的发展。因此，该治疗方案可能为重度肺动脉高压提供一种抗重构治疗方法。
