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.
