Role of angiotensin converting enzyme and other peptidases in in vivo metabolism of kinins.
Arterial plasma kinins and mean arterial pressure were measured in intact and bilaterally nephrectomized rats infused with vehicle or bradykinin to study the role of 1) angiotensin converting enzyme (ACE) and other peptidases and 2) the kidney (a kininase-rich organ) in the metabolism of kinins in vivo. Before the infusion, rats were pretreated with vehicle, enalaprilat (an ACE inhibitor), or a cocktail of kininase inhibitors containing 1) enalaprilat, 2) DL-2-mercaptomethyl-3-guanidinoethyl-thiopropanoic acid (MGTA), a carboxypeptidase N inhibitor, 3) phosphoramidon, a neutral endopeptidase 24.11 inhibitor, and 4) bestatin, an aminopeptidase B inhibitor. In the rats with vehicle (n = 8), the cocktail did not significantly increase endogenous kinins (from 31 +/- 6 to 41 +/- 9 pg/ml, p = 0.94). In the rats infused with bradykinin (peptidase substrate), plasma kinins increased threefold in the group pretreated with the vehicle, 21-fold in the enalaprilat group, and 22-fold in the cocktail group. These increases were doubled by nephrectomy but were not affected by ureteral ligation. In the groups pretreated with the cocktail or enalaprilat, the hypotensive effect of bradykinin was correlated with plasma kinin concentration (r = 0.75, p less than 0.001). After bradykinin infusion was stopped, plasma kinins decreased by half in 10-12 seconds in the rats pretreated with vehicle, enalaprilat, or cocktail. We concluded that ACE and the kidney are important to the metabolism of circulating kinins while carboxypeptidase N, neutral endopeptidase 24.11 and aminopeptidase B are not. We also concluded that other tissue peptidases, not affected by either the above inhibitors or nephrectomy, play an important role in kinin metabolism.
Ishida
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Hypertension Research Division, Henry Ford Hospital, Detroit, Michigan 48202.
Scicli
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Carretero
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D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D007705:Kinins / Q000097:blood / Q000378:metabolism*; D008026:Ligation; D008297:Male; D009392:Nephrectomy; D009994:Osmolar Concentration; D010447:Peptide Hydrolases / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014513:Ureter / Q000502:physiology
D007705:Kinins; D010447:Peptide Hydrolases; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin