Angiotensin-converting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic ACE.

The angiotensin-converting enzyme (ACE) has two natural substrates and two catalytic domains: one cleaving angiotensin I and one inactivating bradykinin. The aim of this study was to investigate the comparative binding affinity of ACE inhibitors for the two binding sites of human endothelial ACE. In vitro binding assays were performed to test the ability of bradykinin, angiotensin I, or various ACE inhibitors (enalaprilat, perindoprilat, quinaprilat, ramiprilat, and trandolaprilat) to displace a saturating concentration of [(125)I]351A, a radiolabeled lisinopril analogue, from ACE binding sites. The calculated IC(50) values for the ACE inhibitors were in the nanomolar range, while those for the natural substrates were in the micromolar range. The bradykinin/angiotensin I selectivity ratios calculated from double displacement experiments were: perindoprilat, 1.44; ramiprilat, 1.16; quinaprilat, 1.09; trandolaprilat, 1.08; enalaprilat, 1.00. The ACE inhibitors generally had higher affinity for the bradykinin than the angiotensin I binding sites, supporting the idea that these agents are primarily inhibitors of bradykinin degradation, and secondarily inhibitors of angiotensin II production. Perindoprilat had the highest selectivity for bradykinin versus angiotensin I binding sites, and enalaprilat has the lowest. These results indicate that there are differences in the affinity of ACE inhibitors toward sites for bradykinin degradation, which could lead to differences in efficacy in cardiovascular disease.