Influence of ischemia and reperfusion on plasma endothelin -1 and endothelin -1 binding sites in pulmonary vasculature.

缺血和再灌注对血浆内皮素-1和肺血管系统内皮素-1结合位点的影响。

• 批准号: 09671390
• 负责人: NAITO Yasuaki
• 金额: $ 1.28万
• 依托单位: Wakayama Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671390/
• 关键词: ischemia-reperfusion injury; lung injury; endothelin; 虚血・再潅流; 肺移植; エンドセリンレセプター

Endothelin is a potent vasoactive peptide produced by vascular endothelial cells and is believed to play an important role in regulation of pulmonary circulation. Various pathologic conditions with pulmonary hypertension have been found to be associated with elevated levels of plasma endothelin-1.To invesitgate the role of endothelin and endothelin binding sites on the pathophysiological response to ischemia-reperfusion injury or lung, we measured a concentration of plasma endothelin-1, NOx (nitrate and nitrite) and pulmonary function (mean pulmonary artery pressure, peak intrapulmonary pressure and oxygen tension of effluent blood) in isolated blood-perfused rabbit lung after ischemia (30 minutes) and reperfusion (60 minutes). l125-labeled endothelin-1 binding of lung tissue was studied using an in vitro autoradiographic technique. Finally, we evaluated the effects of an ET A and ET B non-selective endothelin receptor antagonist, TAK-044, on ischemia-reperfusion injury of lung.Every 2 … More 0 minutes during reperfusion, mean pulmonary artery pressure (mmHg) was 29.3 ± 2.8, 28.7 ± 2.2, 28.9 ± 4.6 in control group (reperfused immediately after hervesting) and 54.0 ± 4.4, 52.7 ± 5.6, 53.5 ± 4.9 in ischemic group (reperfused after 30 minutes ischemia), respectively ; peak intrapulmonary pressure (mmHg) was 11.6 ± 0.9, 11.1 ± 0.9. 11.9 ± 1.1 in control group and 15.5 ± 0.9, 17.5 ± 0.8, 20.3 ± 1.7 in ischemic group, respectively ; oxygen tension of effluent blood (mmHg) was 649.5 ± 13.2, 650.2 ± 26.3, 614.2 ± 26.3 in control group and 588.1 ± 9.2, 497.6 ± 48.9, 356.8 ± 50.3 in ischemic group, respectively.In ischemic group, plasma endothelin-1 was greater (p<0.01) and plasma NOx was lower (p<0.05) than that of control group after 60 minutes reperfusion, the density of ET B binding was decreased in pulmonary artery compared with control group (p<0.05) after 60 minutes reperfusion.In TAK-044 group, TAK-044 (5mg/kg) was adninistered just before ischemia ; every 20 minutes during reperfusion, mean pulmonary artery pressure (mmHg) was 32.2 ± 3.0, 35.0 ±± 1.4, 37.2 ± 1.2, respectively ; peak intrapulmonary pressure (mmHg) was 12.0 ± 0.5, 12.2 ± 0.5, 12.8 ± 0.4, respectively ; oxygen tension of effluent blood (mmHg) was 557.2 ± 15.9, 551.1 ± 11.2, 535.2 ± 15.8, respectively.These results suggest that the increase of plasma endothelin-1, the decrease of plasma NOx and the deminution of ET B binding sites in pulmonary artery play an important role in ischemia-reperfusion injury of lung. TAK-044, an ET A and ET B non-selective endothelin receptor antagonist, has a beneficial effect in protecting the lung from ischemia-reperfusion injury. Less

内皮素是一种由血管内皮细胞产生的有效血管活性肽，被认为在调节肺循环中发挥重要作用。已发现肺动脉高压的各种病理状况与血浆内皮素-1水平升高有关。为了研究内皮素和内皮素结合位点对缺血再灌注损伤或肺的病理生理反应的作用，我们测量了血浆内皮素-1、NOx（硝酸盐和亚硝酸盐）的浓度和肺功能（平均肺动脉） 缺血（30 分钟）和再灌注（60 分钟）后离体血液灌注兔肺中的压力、峰值肺内压和流出血液的氧张力）。使用体外放射自显影技术研究了l125标记的内皮素-1与肺组织的结合。最后，我们评估了 ET A 和 ET B 非选择性内皮素受体拮抗剂 TAK-044 对肺缺血再灌注损伤的影响。再灌注期间每 2 … 更多 0 分钟，对照组（采血后立即再灌注）平均肺动脉压 (mmHg) 为 29.3 ± 2.8、28.7 ± 2.2、28.9 ± 4.6 54.0 缺血组分别为±4.4、52.7±5.6、53.5±4.9（缺血30分钟后再灌注）；峰值肺内压（mmHg）为11.6±0.9、11.1±0.9。对照组分别为11.9±1.1，缺血组分别为15.5±0.9、17.5±0.8、20.3±1.7；对照组流出血氧分压（mmHg）分别为649.5±13.2、650.2±26.3、614.2±26.3，缺血组分别为588.1±9.2、497.6±48.9、356.8±50.3。缺血组血浆内皮素-1较高（p<0.01）和 再灌注60分钟后血浆NOx较对照组降低(p<0.05)，再灌注60分钟后肺动脉ET B结合密度较对照组降低(p<0.05)。 TAK-044组缺血前给予TAK-044(5mg/kg)；再灌注60分钟后肺动脉ET B结合密度较对照组降低(p<0.05)。再灌注期间每20分钟，平均肺动脉压（mmHg）分别为32.2±3.0、35.0±1.4、37.2±1.2；峰值肺内压（mmHg）分别为12.0±0.5、12.2±0.5、12.8±0.4；流出血氧分压(mmHg)分别为557.2±15.9、551.1±11.2、535.2±15.8。这些结果提示血浆内皮素-1的增加、血浆NOx的减少和肺动脉ET B结合位点的减少在肺缺血再灌注损伤中起重要作用。 TAK-044 是一种 ET A 和 ET B 非选择性内皮素受体拮抗剂，具有保护肺部免受缺血再灌注损伤的有益作用。较少的