Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC, USA.
Pulm Pharmacol Ther. 2011 Aug;24(4):407-13. doi: 10.1016/j.pupt.2011.01.009. Epub 2011 Jan 31.
Pulmonary embolism (PE) causes pulmonary hypertension by mechanical obstruction and constriction of non-obstructed vasculature. We tested if experimental PE impairs pulmonary vascular endothelium-dependent dilation via activation of arginase II. Experimental PE was induced in male Sprague-Dawley rats by infusing 25 μm microspheres in the right jugular vein, producing moderate pulmonary hypertension. Shams received vehicle injection. Pulmonary arterial rings were isolated after 18 h and isometric tensions were determined. Dilations were induced with acetylcholine, calcium ionophore A23187 or nitroglycerin (NTG) in pre-contracted rings (phenylephrine). Protein expression was assessed by Western blot and immunohistochemistry. Arginase activity was inhibited by intravenous infusion of N(w)-hydroxy-nor-l-arginine (nor-NOHA). l-Arginine supplementation was also given. Endothelium-dependent dilation responses were significantly reduced in PE vs. vehicle-treated animals (ACh: 50 ± 9% vs. 93 ± 3%; A23187: 19 ± 7% vs. 85 ± 7%, p < 0.05), while endothelium-independent dilations (NTG) were unchanged. Endothelial nitric oxide synthase (eNOS) protein content was unchanged by PE. Expression of arginase II increased 4.5-fold and immunohistochemistry revealed increased arginase II staining. Nor-NOHA treatment and l-arginine supplementation significantly improved pulmonary artery ring endothelium-dependent dilation in PE (ACh: 58 ± 6% PE, 88 ± 6% PE + nor-NOHA, 84 ± 4% PE + l-arginine). Experimental PE impairs endothelium-dependent pulmonary artery dilation, while endothelium-independent dilation remains unchanged. The data support the conclusion that up-regulation of arginase II protein expression contributes to pulmonary artery endothelial dysfunction in this model of experimental PE.
肺栓塞（PE）通过机械阻塞和非阻塞性血管收缩导致肺动脉高压。我们测试了实验性 PE 是否通过激活精氨酸酶 II 来损害肺血管内皮依赖性扩张。雄性 Sprague-Dawley 大鼠通过右颈静脉输注 25 μm 微球来诱导实验性 PE，产生中度肺动脉高压。假手术组接受载体注射。18 小时后分离肺动脉环并测定等长张力。在预先收缩的环（苯肾上腺素）中用乙酰胆碱、钙离子载体 A23187 或硝化甘油（NTG）诱导扩张。通过静脉输注 N（w）-羟基-nor-l-精氨酸（nor-NOHA）抑制精氨酸酶活性。还给予 l-精氨酸补充。与载体处理的动物相比，PE 中的内皮依赖性扩张反应明显降低（ACh：50 ± 9%比 93 ± 3%；A23187：19 ± 7%比 85 ± 7%，p <0.05），而内皮非依赖性扩张（NTG）保持不变。PE 对内皮型一氧化氮合酶（eNOS）蛋白含量没有影响。精氨酸酶 II 的表达增加了 4.5 倍，免疫组织化学显示精氨酸酶 II 染色增加。Nor-NOHA 治疗和 l-精氨酸补充显著改善了 PE 中的肺动脉环内皮依赖性扩张（ACh：PE 中的 58 ± 6%，PE+nor-NOHA 中的 88 ± 6%，PE+l-精氨酸中的 84 ± 4%）。实验性 PE 损害了内皮依赖性肺动脉扩张，而内皮非依赖性扩张保持不变。这些数据支持这样的结论，即精氨酸酶 II 蛋白表达的上调导致了这种实验性 PE 模型中的肺动脉内皮功能障碍。
