PHARMACOLOGICAL DATA REVEAL THE HETEROGENEITY OF ANGIOTENSIN-CONVERTING ENZYME ACCORDING TO ITS SOURCE (LUNG VERSUS HEART)

Angiotensin-converting enzyme (ACE) has 2 different active sites: a C- site (in the carboxy terminal region) and an N-site (in the amino term inal 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 r elated to binding differences to the C- and N-sites. We labeled Ro31-8 472, a cilazapril derivative, which has the same affinity for the 2 AC E sites. Binding of I-125-Ro31-8472 to human left ventricle and lung p lasma membranes was saturable, inhibited by ethylene diaminetetraaceti c acid and displayed affinities of 360 +/- 41 pM in heart and 320 +/- 51 pM in lung. For captopril the Hill slope was 0.57 +/- 0.03 for hear t 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 isot herms. 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 capto pril had greater affinity for the high-affinity sites of lung than hea rt (9.40 and 8.85, respectively). The pK(i) of these drugs for the sec ond site was 7.18-7.90 for each drug in each tissue. The affinity of R o31-8472 was similar for heart and lung, but enalaprilat had greater a ffinity 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); o ther inhibitors are site- and tissue-nonselective (Ro31-8472) or site nonselective but tissue-selective (enalaprilat).