Kallidin- and Bradykinin-Degrading Pathways in Human Heart

Abstract

Background-Since kinins kallidin (KD) and bradykinin (BK) appear to have cardioprotective effects ranging from improved hemodynamics to antiproliferative effects, inhibition of kinin-degrading enzymes should potentiate such effects. Indeed, it is believed that this mechanism is partly responsible for the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors. In the heart, enzymes other than ACE may contribute to local degradation of kinins. The purpose of this study was to investigate which enzymes are responsible for the degradation of KD and BK in human heart tissue. Methods and Results-Cardiac membranes were prepared from the left ventricles of normal (nϭ5) and failing (nϭ10) hearts. The patients had end-stage congestive heart failure as the result of coronary heart disease or idiopathic dilated cardiomyopathy. Heart tissue was incubated with KD or BK in the presence or absence of enzyme inhibitors. We found no difference in the enzymes responsible for kinin metabolism or their activities between normal and failing hearts. Thus KD was mostly converted into BK by the aminopeptidase M-like activity. When BK was used as substrate, it was converted into an inactive metabolite BK-(1-7) mostly (80% to 90%) by the neutral endopeptidase (NEP) activity, with ACE unexpectedly playing only a minor role. The low enzymatic activity of ACE in the cardiac membranes, compared with that of NEP, was not due to chronic ACE inhibitor therapy, because the cardiac ACE activities of patients, whether receiving ACE inhibitors or not, and of normal subjects were all equal. Conclusions-The present in vitro study shows that in human cardiac membranes, the most critical step in kinin metabolism, that is, inactivation of BK, appears to be mediated mostly by NEP. This observation suggests a role for NEP in the local control of BK concentration in heart tissue. Thus inhibition of cardiac NEP activity could be cardioprotective by elevating the local concentration of BK in the heart. (Circulation. 1999;99:1984-1990.)

Losartan Increases Bradykinin Levels in Hypertensive Humans

“…Bradykinin and kallidin peptides may also be metabolized by different enzymes. Kokkonen et al 37 report that kallidin metabolism by cardiac membranes is via aminopeptidase M-like activity, whereas bradykinin is metabolized by NEP.…”

Neutral Endopeptidase Is Activated in Cardiomyocytes in Human Aortic Valve Stenosis and Heart Failure

“…1 In the human myocardial interstitium, NEP represents the major bradykinin degrading enzyme. 2 Along with the renin-angiotensin system (RAS) and the sympathetic nervous system, the kallikrein-kinin system is involved in the onset and progression of heart failure and ventricular remodeling after myocardial infarction. 3 Kinins reduce left ventricular hypertrophy and fibrosis and prevent progression of heart failure.…”

Potentiation of des-Arg9-Kallidin-Induced Vasoconstrictor Responses by Metallopeptidase Inhibition in Isolated Human Umbilical Artery

“…NEP, a membrane-bound M13 zinc metallopeptidase, was first detected in the brush border of animal kidney by Kerr and Kenny (1974). Since then, NEP presence has been described in many vascular tissues, such as rat aorta smooth muscle, adventitial and endothelial cells (Gonzá lez et al, 1998), human endothelial cells (Llorens-Cortes et al, 1992), and cardiomyocytes (Kokkonen et al, 1999). Gafford et al (1983) have shown that the selective BKB 2 receptor agonist BK is hydrolyzed by NEP.…”

“…This enzyme has been described in endothelial cells of many origins (Erdos, 1990), in human heart (Kokkonen et al, 1999), and in rat aorta smooth muscle (Arnal et al, 1994). ACE cleaves the C-terminal tripeptide from BKB 1 receptor agonists, yielding BK 1-5 but at a slower rate and with less affinity than the removal of the C-terminal dipeptide from BK (Marceau et al, 1998).…”