Department of Pharmacology, Faculty of Health Sciences, Aarhus University, Aarhus C, Denmark.
Eur J Pharmacol. 2010 Nov 25;647(1-3):147-54. doi: 10.1016/j.ejphar.2010.08.032. Epub 2010 Sep 7.
The present study investigated whether BAY 41-2272(5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine), a novel pyrazolopyridine that activates guanylyl cyclase and sensitizes the enzyme towards nitric oxide (NO), inhibits the development of pulmonary hypertension. BAY 41-2272 (1 or 10 mg/kg/day) was administered intraperitoneally, and sildenafil (25 mg/kg/day), an inhibitor phosphodiesterase type 5, was given in the drinking water to rats kept under chronic hypobaric hypoxia for two weeks. Right ventricular systolic pressure and hypertrophy, degree of muscularization and relaxation of pulmonary arteries were measured, and immunoblotting was performed. Chronic hypoxia increased right ventricular systolic pressure and expression of soluble guanylyl cyclase and phosphorylated vasodilator-stimulated phosphoprotein (VASP-P(ser239)). BAY 41-2272 prevented hypoxia-induced increase in right ventricular systolic pressure and right ventricular hypertrophy to the same extent as sildenafil. Only sildenafil significantly decreased hypoxia-induced muscularization of pulmonary arteries. Expressed relative to soluble guanylyl cyclase expression, VASP-P(ser239) was increased in lungs from rats treated with BAY 41-2272. Acutely BAY 41-2272 caused pulmonary as well as systemic vasodilatation. In the chronic setting systemic blood pressure was not different to baseline at trough after intraperitoneally administered BAY 41-2272. BAY 41-2272 vasorelaxation in isolated pulmonary resistance arteries was inhibited by an inhibitor of guanylyl cyclase, ODQ (1H-[1,2,4] oxadiazolo[4,3-a]quinoxaline-1-one), and of Na(+)-K(+)-ATPase, ouabain. In conclusion, in an adult rat model of chronic hypoxic pulmonary hypertension, BAY 41-2272 to a similar degree as sildenafil prevents pulmonary hypertension. Thus, BAY 41-2272 may provide a novel therapeutic compound for treating chronic hypoxic pulmonary hypertension.
本研究旨在探讨新型吡唑并嘧啶类化合物 BAY 41-2272（5-环丙基-2-[1-(2-氟苄基)-1H-吡唑并[3,4-b]吡啶-3-基]-嘧啶-4-胺）是否能抑制肺动脉高压的发生。BAY 41-2272（1 或 10mg/kg/天）通过腹腔注射给药，同时给予抑制剂西地那非（25mg/kg/天）至慢性低压低氧大鼠的饮用水中。两周后，测量右心室收缩压和肥厚、肺动脉肌化和松弛程度，并进行免疫印迹分析。慢性低氧增加了右心室收缩压、可溶性鸟苷酸环化酶和磷酸化血管扩张刺激磷蛋白（VASP-P（ser239））的表达。BAY 41-2272 能防止右心室收缩压和右心室肥厚的增加，与西地那非效果相同。只有西地那非能显著降低低氧诱导的肺动脉肌化。与可溶性鸟苷酸环化酶表达相比，BAY 41-2272 治疗的大鼠肺中 VASP-P（ser239）表达增加。BAY 41-2272 能迅速引起肺和全身血管舒张。在慢性环境中，腹腔注射 BAY 41-2272 后，全身血压在低谷时与基线相比没有差异。BAY 41-2272 对分离的肺阻力血管的血管舒张作用被鸟苷酸环化酶抑制剂（1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮，ODQ）和 Na(+)-K(+)-ATP 酶抑制剂哇巴因抑制。综上所述，在慢性低氧性肺动脉高压的成年大鼠模型中，BAY 41-2272 与西地那非具有相似的效果，可预防肺动脉高压。因此，BAY 41-2272 可能为治疗慢性低氧性肺动脉高压提供一种新的治疗化合物。
