Proteases involved in the metabolism of angiotensin II, bradykinin, calcitonin gene-related peptide (CGRP), and neuropeptide Y by vascular smooth muscle cells.

To understand the regulation of the vasoactive peptides bradykinin, angiotensin II, calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY), their proteolytic catabolism by cultured rat aortic vascular smooth muscle cells and A7r5 cells was investigated. Endopeptidase-24.11 (EC 3.4.24.11, CD 10) was responsible for the final inactivation of bradykinin, angiotensin II, and CGRP, but not of NPY, which was degraded by a different metallo-endopeptidase. Exopeptidases, namely the aminopeptidases A (EC 3.4.11.7), N (EC 3.4.11.2, CD 13), and P (EC 3.4.11.9) and the carboxypeptidases M (EC 3.4.17.12) and P (EC 3.4.17.16), were important for their differential, receptor subtype-specific activation or inactivation. Aminopeptidase A and N generated angiotensins III and IV from angiotensin II. Aminopeptidase P liberated the terminal amino acids from bradykinin and NPY, yielding the Y2 receptor specific-agonist NPY(2-36). Carboxypeptidase P produced AT II(1-7) and carboxypeptidase M produced the BK1 receptor agonist [des-Arg9]bradykinin. Thus, peptidases at the surface of vascular smooth muscle cells exert a complex influence on the level of biologically active vasoactive peptides.