A novel stable inhibitor of endopeptidases EC 3.4.24.15 and 3.4.24.16 potentiates bradykinin-induced hypotension.
We have developed a novel inhibitor of the metalloendopeptidases EC 3.4.24.15 (EP24.15) and EC 3.4.24.16 (EP24.16), N-[1-(R, S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA2), in which alpha-aminoisobutyric acid (Aib) is substituted for an alanine in a well-described but unstable inhibitor, cFP-AAY-pAB. This substitution increases the resistance of the inhibitor to degradation without altering potency. In the present study, we investigated the effects of JA2 (5 mg/kg) on the responses of mean arterial pressure to bradykinin, angiotensin I, and angiotensin II in conscious rabbits. The depressor responses to both low (10 ng/kg) and high (100 ng/kg) doses of bradykinin were increased 7.0+/-2. 7-fold and 1.5+/-0.3-fold, respectively, during the 30 minutes after JA2 administration (mean+/-SEM, n=8). Bradykinin potentiation was undiminished 4 hours after JA2 injection. In contrast, the hypertensive effects of angiotensins I and II were unaltered, indicating that the bradykinin-potentiating effects were not due to angiotensin-converting enzyme inhibition. These data suggest that JA2 is not only a potent and specific inhibitor of EP24.15 and EP24. 16 but is also stable in vivo. Furthermore, the potentiation of bradykinin-induced hypotension by JA2 suggests for the first time a role for one or both of these peptidases in the metabolism of bradykinin in the circulation.
Smith
A I
AI
Baker Medical Research Institute, Melbourne, Australia. Ian.Smith@Baker.edu.au
Lew
R A
RA
Shrimpton
C N
CN
Evans
R G
RG
Abbenante
G
G
D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000009:adverse effects*; D004151:Dipeptides / Q000494:pharmacology*; D004341:Drug Evaluation; D004357:Drug Synergism; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology*; D007457:Iodine Radioisotopes; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D004151:Dipeptides; D007457:Iodine Radioisotopes; C404562:N-carboxy-3-phenylpropyl-alanyl-aminoisobutyric acid-tyrosyl-aminobenzoate; D011480:Protease Inhibitors; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000803:Angiotensin I; D001920:Bradykinin