Kallidin- and bradykinin-degrading pathways in human heart: degradation of kallidin by aminopeptidase M-like activity and bradykinin by neutral endopeptidase.
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.


RESULTS
Cardiac membranes were prepared from the left ventricles of normal (n=5) and failing (n=10) 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.
Kokkonen
J O
JO
Wihuri Research Institute, Helsinki, Finland. jorma.kokkonen@pp.fimnet.fi
Kuoppala
A
A
Saarinen
J
J
Lindstedt
K A
KA
Kovanen
P T
PT
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism*; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002216:Captopril / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D007609:Kallidin / Q000378:metabolism*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology*; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology; D013379:Substrate Specificity
D000806:Angiotensin-Converting Enzyme Inhibitors; D000900:Anti-Bacterial Agents; D004151:Dipeptides; D006020:Glycopeptides; D008565:Membrane Proteins; D010455:Peptides; D011480:Protease Inhibitors; C060631:Sch 39370; D007609:Kallidin; C016977:amastatin; D002216:Captopril; D018826:CD13 Antigens; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D007930:Leucine; C012211:ubenimex; D001920:Bradykinin; C008890:phosphoramidon