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Summary: Angiotensin-converting enzyme (ACE) has two enzymatically active domains: a C-domain in the carboxy terminal region and an N-domain in the amino terminal region. We based the pharmacologic characterization of these sites on the rat testis-lung model. In testis, only a truncate form of ACE is present (C-site), whereas both N- and C-sites are present in lung. In this model, captopril was shown to be N-selective and delaprilat to be C-selective. Ro 31-8472, a cilazapril derivative, and enalaprilat proved to be not site selective. We used these drugs to evaluate the affinity of C and N sites in various human tissues involved in the cardiovascular actions of ACE and used [125I]Ro31-8472 as ligand. The number and affinity of ACE binding sites were 17,680 /- 2,345 fmol/mg protein (Kd = 0.32 /- 0.04 nM) in lung, 560 /- 65 (Kd = 0.36 /- 0.05 nM) in heart, 237 /- 51 (Kd = 0.37 0.06 nM) in coronary artery, 236 /- 63 (Kd = 0.14 /- 0.05 nM) in saphenous vein, and 603 /- 121 (Kd = 0.50 /- 0.06 nM) in mammary artery. The affinity (pKi) of captopril for the N sites ranged from 9.40 /- 0.14 (lung) to 8.41 /- 0.10 (coronary artery). The affinity for the C-site by delaprilat ranged from 9.97 /- 0.15 (coronary artery) to 9.10 /- 0.14 (mammary artery). Therefore, the affinity of C- and N- sites of ACE for ACE inhibitor (ACEI) drugs is different according to the organ involved. Because ACE is a glycosylated enzyme and glycosylation is organ dependent, we suggest that organ-specific glycosylation affects the binding characteristics of ACE inhibitors to N- or C-site of human tissular ACE.

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