Bradykinin metabolism in the postinfarcted rat heart: role of ACE and neutral endopeptidase 24.11

The respective role of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) in the degradation of bradykinin (BK) has been studied in the infarcted and hypertrophied rat heart. Myocardial infarction (MI) was induced in rats by left descendant coronary artery ligature. Animals were killed, and hearts were sampled 1, 4, and 35 days post-MI. BK metabolism was assessed by incubating synthetic BK with heart membranes from sham hearts and infarcted (scar) and noninfarcted regions of infarcted hearts. The half-life ( t ½) of BK showed significant differences among the three types of tissue at 4 days [sham heart (114 ± 7 s) > noninfarcted region (85 ± 4 s) > infarcted region (28 ± 2 s)] and 35 days post-MI [sham heart (143 ± 6 s) = noninfarcted region (137 ± 9 s) > infarcted region (55 ± 4 s)]. No difference was observed at 1 day post-MI. The participation of ACE and NEP in the metabolism of BK was defined by preincubation of the membrane preparations with enalaprilat, an ACE inhibitor, and omapatrilat, a vasopeptidase inhibitor that acts by combined inhibition of NEP and ACE. Enalaprilat significantly prevented the rapid degradation of BK in every tissue type and at every sampling time. Moreover, omapatrilat significantly increased the t ½ of BK compared with enalaprilat in every tissue type and at every sampling time. These results demonstrate that experimental MI followed by left ventricular dysfunction significantly modifies the metabolism of exogenous BK by heart membranes. ACE and NEP participate in the degradation of BK since both enalaprilat and omapatrilat have potentiating effects on the t ½ of BK.

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

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-Arg9-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-Arg9-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-Arg9-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-Arg9-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-Arg9-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.