Inhibition of angiotensin converting enzyme by the metalloendopeptidase 3.4.24.15 inhibitor c-phenylpropyl-alanyl-alanyl-phenylalanyl-p-aminobenzoate.
Inhibitors of metallopeptidases may represent new alternatives in the treatment of cardiovascular disease. Recent investigations have linked the hypotensive properties of the metalloendopeptidase 3.4.24.15 (MEP 24.15) inhibitor c-phenylpropyl-alanyl-alanyl-phenylalanyl-para-aminobenzoate (cFP-A-A-F-pAB) to the attenuation of bradykinin metabolism. However, since angiotensin converting enzyme (ACE) is widely recognized to contribute to the metabolic clearance of bradykinin, we characterized the specificity of cFP-A-A-F-pAB towards ACE. We also determined whether cFP-A-A-F-pAB inhibits the conversion of angiotensin I (Ang I) to Ang II by pulmonary ACE. The ACE activity toward the synthetic substrate hippuryl-histidine-leucine (Hip-His-Leu) was measured in vitro using both a purified lung preparation and pooled rat serum. The ACE activity was inhibited at increasing concentrations of the MEP 24.15 inhibitor. Kinetic analysis revealed that cFP-A-A-F-pAB competitively inhibited pulmonary ACE with a Ki of 0.19 microM. In rat serum, cFP-A-A-F-pAB also competitively inhibited ACE. The hydrolysis of Ang I into Ang II by pulmonary ACE was inhibited to a similar extent by both cFP-A-A-F-pAB and the ACE inhibitor MK 422. These findings are the first to show that the MEP 24.15 inhibitor cFP-A-A-F-pAB also inhibits ACE. We suggest that the reported hypotensive actions of cFP-A-A-F-pAB may be due to the reduction in both bradykinin metabolism and Ang II generation arising from the blockade of ACE.
Chappell
M C
MC
Department of Brain and Vascular Research, Cleveland Clinic Foundation, OH 44195-5070.
Welches
W R
WR
Brosnihan
K B
KB
Ferrario
C M
CM
D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000201:enzymology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; C064939:N-(1-carboxy-3-phenylpropyl)-alanyl-alanyl-phenylalanine-4-aminobenzoate; D007703:Peptidyl-Dipeptidase A; D008666:Metalloendopeptidases