Contribution of angiotensin-converting enzyme to the cardiac metabolism of bradykinin: an interspecies study

1 Faculté de Pharmacie, Université de Montréal, Montreal H3C 3J7; 2 Centre de Recherche (Université Laval), Hôtel-Dieu de Québec, Quebec, Quebec, Canada G1R 2J7; and Service d'Anesthésie-Réanimation, Centre Hospitalier Universitaire de Liège, B.35-B 4000, Liège, Belgium The role of angiotensin-converting enzyme (ACE) in the metabolism of bradykinin (BK) has been studied in several tissues. However, and contrary to angiotensin I, the metabolism of BK at the cardiac level has not been investigated. In this study, we define the participation of ACE in the carboxy-terminal degradation of BK in heart membranes of the dog, human, rabbit, and rat. The calculation of the kinetic parameters characterizing the metabolism of BK and the generated des-Arg 9 -BK can be summarized as follows: the half-life ( t 1/2 ) of BK [dog (218 ± 32 s) > human (143 ± 9 s) = rat (150 ± 4 s) > rabbit (22 ± 2 s)] and of des-Arg 9 -BK [dog (1,042 ± 40 s) > human (891 ± 87 s) > rat (621 ± 65 s) > rabbit (89 ± 8 s)] both showed significant differences according to species. Enalaprilat, an ACE inhibitor, significantly prevented the rapid degradation of BK and des-Arg 9 -BK in all species studied, whereas retrothiorphan, a neutral endopeptidase inhibitor, and losartan, an angiotensin II type I receptor antagonist, did not affect this metabolism. The relative importance of ACE in the cardiac metabolism of BK was species related: dog (68.4 ± 3.2%) = human (72.2 ± 2.0%) > rabbit (47.7 ± 5.0%) = rat (45.3 ± 3.9%). ACE participation in the metabolism of des-Arg 9 -BK was as follows: rabbit (57.0 ± 4.0%) > dog (39.9 ± 8.8%) = human (25.4 ± 5.5%) = rat (36.0 ± 7.0%). The participation of cardiac kininase I (carboxypeptidase M) in the transformation of BK into des-Arg 9 -BK was minor: human (2.6 ± 0.1%) > dog (0.9 ± 0.1%) = rabbit (1.0 ± 0.1%) = rat (1.0 ± 0.1%). These results demonstrate that ACE is the major BK-degrading enzyme in cardiac membranes. However, the metabolism of exogenous BK by heart membranes is species dependent. Our observations could explain some discrepancies regarding the contribution of kinins in the cardioprotective effects of ACE inhibitors. angiotensin-converting enzyme inhibitor; bradykinin metabolism; cardioprotection