AFFINITY OF ANGIOTENSIN I-CONVERTING ENZYME (ACE) INHIBITORS FOR N-BINDING AND C-BINDING SITES OF HUMAN ACE IS DIFFERENT IN HEART, LUNG, ARTERIES, AND VEINS

Angiotensin-converting enzyme (ACE) has two enzymatically active domai ns: a C-domain in the carboxy terminal region and an N-domain in the a mino terminal region. We based the pharmacologic characterization of t hese sites on the rat testis-lung model. In testis, only a truncate fo rm 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 del aprilat to be C-selective. Ro 31-8472, a cilazapril derivative, and en alaprilat proved to be not site selective. We used these drugs to eval uate the affinity of C and N sites in various human tissues involved i n the cardiovascular actions of ACE and used [I-125]Ro31-8472 as ligan d. The number and affinity of ACE binding sites were 17,680 +/- 2,345 fmol/mg protein (K-d = 0.32 +/- 0.04 nM) in lung, 560 +/- 65 (K-d = 0. 36 +/- 0.05 nM)in heart, 237 +/- 51 (K-d = 0.37 +/- 0.06 nM) in corona ry artery, 236 +/- 63 (K-d = 0.14 +/- 0.05 nM) in saphenous vein, and 603 +/- 121 (K-d = 0.50 +/- 0.06 nM) in mammary artery. The affinity ( pK(i)) of captopril for the N sites ranged from 9.40 +/- 0.14 (lung) t o 8.41 +/- 0.10 (coronary artery). The affinity for the C-site by dela prilat ranged from 9.97 +/- 0.15 (coronary artery) to 9.10 +/- 0.14 (m ammary artery). Therefore, the affinity of C- and N-sites of ACE for A CE inhibitor (ACEI) drugs is different according to the organ involved . Because ACE is a glycosylated enzyme and glycosylation is organ depe ndent, we suggest that organ-specific glycosylation affects the bindin g characteristics of ACE inhibitors to N- or C-site of human tissular ACE.