Angiotensin homologs and analogs as inhibitors of rabbit pulmonary angiotensin-converting enzyme.

The angiotensin-converting enzyme from rabbit lung was purified to a homogeneous protein. The molecular weight of the enzyme or its subunits in sodium dodecyl sulfate-polyacrylamide gel electrophoresis was established as 180,000. Converting enzyme contained about 8% (w/w) hexoses (based on glucose). The K,,, values for the hydrolysis of angiotensin I and [desAspllangiotensin I by the purified enzyme were 80 and 30 pa, respectively, at 37”. Chloride ion appeared to increase the affinity of converting enzyme for angiotensin I and [desAsp’langiotensin I. The Bothrops ,jararaca nonapeptide and angiotensin III were competitive inhibitors of the hydrolysis of angiotensin I or Ides-Asp’langiotensin I. The K, values obtained for angiotensin III and B. ,jaruruca nonapeptide did not change significantly as different enzyme substrates were employed. Several angiotensin II receptor blockers were found to be potent competitive inhibitors of converting enzyme. The affinity of angiot.ensin II analogs for converting enzyme was influenced strongly by the charge of the NH,-terminal amino acid residue. Inhibitory activity was enhanced by neutral or basic substituents and attenuated by acidic NH,terminal residues. Position 8 of angiotensin II is important for the interaction with the converting enzyme. The affinity of the enzyme for angiotensin II analogs was decreased by substituting analogs with branched aliphatic side chains at the COOH terminus of the inhibitor molecule. These results indicate that Ides-Asp’Jangiotensin I is a substrate for rabbit pulmonary converting enzyme. The data are consistent with the postulated alternative pathway for the formation of angiotensin III from Ides-Aspllangiotensin I, a product of the hydrolysis of angiotensin I by aminopeptidase. Some angiotensin receptor blockers may act in uiuo or in citro as modulators of converting enzyme activity.