Structural Requirements for Substrates and Inhibitors of Angiotensin I-Converting Enzyme In Vivo and In Vitro

Abstract

The mechanism of action of peptide inhibitors on angiotensin I-converting enzyme (Al-converting enzyme) was studied in relation to the substrate requirements of the enzyme in vivo in the dog lung and in vitro in plasma. 1-d-Asp-8-Ile-AI prepared by the solid-phase technique was compared with the known peptide inhibitors of Al-converting enzyme. BPP5a (Pyr-Lys-Trp-Ala-Pro) and SQ 20881 (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro)125I-1-d-Asp-8-Ile-AI was evaluated for susceptibility to cleavage by the Al-converting enzyme. In vitro and in vivo, 125I-1-d-Asp-8-Ile-AI or BPP5a in 50,000-fold molar excess produced only a slight delay in conversion of 1251-AI to 125I-angiotension II (AII); SQ 20881 blocked conversion completely. In vivo, l-d-Asp-8-Ile-AI or BPP5a injected into the pulmonary circulation in 250-fold molar excess (250 nmole/kg) did not cause a diminution in the pressor response to AI administered 30 seconds later; SQ 20881 blocked the pressor response to Al for 60-90 minutes. 1-d-Asp-8-Ile-AI was a poor...