Inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes.
Synthesis of angiotensin-converting enzyme is induced during its chronic inhibition. Like angiotensin-converting enzyme, neutral endopeptidase (EC 3.4.24.11) is a plasma membrane peptidase. We studied changes of the two enzymes in lung, kidney and serum in a coronary ligation model of experimental congestive heart failure, and during chronic inhibition of the enzymes. Coronary-ligated rats (n = 19) and sham-operated controls (n = 18) were given SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine], a specific neutral endopeptidase inhibitor (n = 13), captopril (n = 12), or vehicle (n = 12) for 4 days, and exsanguinated. Pulmonary angiotensin-converting enzyme was induced both by captopril (52% compared to vehicle) and by SCH 34826 (21%). Serum angiotensin-converting enzyme was induced by captopril (44%). Neutral endopeptidase was induced in lung by captopril (73%), and in kidney by SCH 38426 (32%). Compared to controls, the relative heart weight of rats with heart failure was increased by 29%, and the plasma level of atrial natriuretic peptide elevated by 74%, but enzyme activities were not different. We conclude that, in the rat, separate inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes, and that the induction varies in different tissues. Alterations in the substrates of the two enzymes, e.g. in bradykinin, might cause these changes.
Minerva Institute for Medical Research, Helsinki, Finland.
K
K
Helin
I
I
Tikkanen
U
U
Hohenthal
F
F
Fyhrquist
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology; D004148:Dioxolanes / Q000008:administration & dosage / Q000494:pharmacology; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D006333:Heart Failure / Q000201:enzymology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008026:Ligation; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis; D012083:Renin / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D004148:Dioxolanes; D004151:Dipeptides; C056319:Sch 34826; D009320:Atrial Natriuretic Factor; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D015260:Neprilysin