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(Hypertension. 2000;35:626.)
© 2000 American Heart Association, Inc.

Scientific Contributions

A Novel Stable Inhibitor of Endopeptidases EC 3.4.24.15 and 3.4.24.16 Potentiates Bradykinin-Induced Hypotension

A. Ian Smith; Rebecca A. Lew; Corie N. Shrimpton; Roger G. Evans; Giovanni Abbenante

From Baker Medical Research Institute, Melbourne, Australia (A.I.S., R.A.L., C.N.S.); the Department of Physiology, Monash University, Clayton, Australia (R.G.E.); and the Centre for Drug Design and Development, University of Queensland, St. Lucia, Australia (G.A.).

Correspondence to Dr A.I. Smith, Baker Medical Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria, Australia 8008. E-mail Ian.Smith{at}Baker.edu.au

Abstract—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 -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.

Key Words: bradykinin • angiotensin • circulation • angiotensin-converting enzyme • endopeptidase inhibition

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