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Angiotensin-converting enzyme (ACE) has 2 different active sites: a C-site (in the carboxy terminal region) and an N-site (in the amino terminal part). Some ACE inhibitors have a relatively greater affinity for the C-sites, whereas others bind to the 2 sites with equal affinity. The different ontogenesis of lung and heart endothelial cells can be related to binding differences to the C- and N-sites. We labeled Ro31 – 8472, a cilazapril derivative, which has the same affinity for the 2 ACE sites. Binding of 125 I-Ro31-8472 to human left ventricle and lung plasma membranes was saturable, inhibited by ethylene diaminetetraacetic acid and displayed affinities of 360 ± 41 p M in heart and 320 ± 51 p M in lung. For captopril the Hill slope was 0.57 ± 0.03 for heart and 0.48 ± 0.05 for lung; for delaprilat, a nonsulfhydryl analogue of captopril, the slope was 0.43 ± 0.05 for heart and 0.55 ± 0.05 for lung. These drugs were characterized by biphasic competition isotherms. The Hill slope of enalaprilat was 1.01 ± 0.06 for heart and 0.93 ± 0.06 for lung, and Ro31-8472 had a slope of 0.97 ± 0.04 for heart and 0.93 ± 0.03 for lung. The affinity of ACE inhibitors with Hill slope different from unity varied according to the source of ACE; in fact, delaprilat had greater affinity for the high-affinity sites of heart than lung (pK i , 9.89 and 9.47, respectively), whereas captopril had greater affinity for the high-affinity sites of lung than heart (9.40 and 8.85, respectively). The pK i of these drugs for the second site was 7.18–7.90 for each drug in each tissue. The affinity of Ro31-8472 was similar for heart and lung, but enalaprilat had greater affinity for lung ACE (pK i = 9.21) than heart ACE (pK i = 8.76). In conclusion, different ACE inhibitors can interact with the ACE binding sites exhibiting a selectivity that varies depending on the source of the enzyme. Some drugs are site- and tissue-selective (delaprilat is C-site and heart-selective; captopril is C-site and lung-selective); other inhibitors are site- and tissue-nonselective (Ro31-8472) or site nonselective but tissue-selective (enalaprilat).