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 (A ib) is substituted for an alanine in a well-described but unstable inhibito r, cFP-AAY-pAB. This substitution increases the resistance of the inhibitor to degradation without altering potency. In the present study, we investig ated the effects of JA2 (5 mg/kg) on the responses of mean arterial pressur e to bradykinin, angiotensin I, and angiotensin II in conscious rabbits. Th e 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, respective ly, during the 30 minutes after JA2 administration (mean+/-SEM, n=8). Brady kinin potentiation was undiminished 4 hours after JA2 injection. In contras t, the hypertensive effects of angiotensins I and II were unaltered, indica ting that the bradykinin-potentiating effects were not due to angiotensin-c onverting enzyme inhibition. These data suggest that JA2 is not only a pote nt and specific inhibitor of EP24.15 and EP24.16 but is also stable in vivo . Furthermore, the potentiation of bradykinin-induced hypotension by JA2 su ggests for the first time a role for one or both of these peptidases in the metabolism of bradykinin in the circulation.