NOVEL ROUTE FOR BRADYKININ DEGRADATION IN LUNG

肺部缓激肽降解的新途径

基本信息

批准号：
2221964
负责人：
WILLIAM H SIMMONS
金额：
$ 14.36万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-08-01 至 1995-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2221964
关键词：
aminopeptidase animal tissue bradykinin chemical cleavage enzyme mechanism enzyme structure high performance liquid chromatography hormone inhibitor isolation perfusion laboratory rat lung membrane proteins protease inhibitor protein degradation protein sequence radiotracer tissue /cell culture vascular endothelium

项目摘要

Bradykinin, a circulating vasoactive peptide, is degraded almost completely during a single passage through the lung. The enzymes responsible for bradykinin metabolism are located on the plasma membrane of vascular endothelial cells. While angiotensin converting enzyme has been implicated in this process, a considerable amount of evidence suggests that other less-well characterized enzymes are also significantly involved. We have identified a novel mechanism of bradykinin degradation in lung which involves cleavage of the Arg-1-Pro-2 -bond by aminopeptidase P. This membrane-bound enzyme is likely to be highly specific for bradykinin, and its importance has been demonstrated both in vitro and in situ using the isolated perfused rat lung model. In order to Fetter understand the role of this enzyme in regulating bradykinin function, aminopeptidase P will be purified to homogeneity and then extensively characterized in terms of its physical and enzymatic properties. A search will be made for potent and highly selective inhibitors of aminopeptidase P. The inhibitors will then be tested for their ability to prevent degradation of bradykinin in the isolated perfused rat lung. This information may provide the rationale for the control of both the plasma levels and physiological actions of circulating bradykinin.

Bradykinin是一种循环的血管活性肽，几乎被降解完全在通过肺部的单个通道中。酶负责缓激肽代谢的质膜位于质膜上血管内皮细胞的。而血管紧张素转化酶具有与此过程有关，有很多证据表明其他特征较小的酶也是大量参与。我们已经确定了一种新颖的机制肺中的松曲蛋白降解，涉及Arg-1-Pro-2的裂解 - 氨基肽酶的束缚。该膜结合的酶可能是对Bradykinin的高度特异性及其重要性已被证明在体外和原位使用孤立的灌注大鼠肺模型。在为了束缚该酶在调节中的作用心动激肽功能，氨基肽酶P将被纯化为均匀性和然后以其物理和酶促的广泛特征特性。将进行有效和高度选择性的搜索氨基肽酶P的抑制剂。然后将测试抑制剂它们防止在孤立的灌注的老鼠肺。此信息可能为控制血浆水平和生理作用循环的心动激肽。