Pharmacologic data reveal the heterogeneity of anaiotensin-converting enzyme according to its source (lung versus heart)

Abstract

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 clizapril derivative, which has the same affinity for the 2 ACE sites. Binding of 125I-Ro31-8472 to human left ventricle and lung plasma membranes was saturable, inhibited by ethylene diaminetetraacetic 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 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 (pKi, 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).(ABSTRACT TRUNCATED AT 250 WORDS)