A novel stable inhibitor of endopeptidases EC 3.4.24.15 and 3.4.24.16 potentiates bradykinin-induced hypotension.

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 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.

• Authors: A I Smith, R A Lew, C N Shrimpton, R G Evans, G Abbenante
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 35 Issue 2 Pg. 626-30 (Feb 2000) ISSN: 1524-4563 [Electronic] United States
• PMID: 10679508 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dipeptides
• Iodine Radioisotopes
• N-carboxy-3-phenylpropyl-alanyl-aminoisobutyric acid-tyrosyl-aminobenzoate
• Protease Inhibitors
• Vasoconstrictor Agents
• Angiotensin II
• Angiotensin I
• Bradykinin

Topics

• Angiotensin I (pharmacology)
• Angiotensin II (pharmacology)
• Animals
• Blood Pressure (drug effects)
• Bradykinin (adverse effects)
• Dipeptides (pharmacology)
• Drug Evaluation
• Drug Synergism
• Heart Rate (drug effects)
• Hypotension (chemically induced, physiopathology)
• Iodine Radioisotopes
• Protease Inhibitors (metabolism, pharmacology)
• Rabbits
• Vasoconstrictor Agents (pharmacology)