Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor

Sarah E. Telford, A. Ian Smith, Rebecca A. Lew, Rose B. Perich, Anna C. Madden, Roger G. Evans

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Abstract

1 We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N‐[1‐(R,S)‐carboxy‐3‐phenylpropyl]‐Ala‐Ala‐Tyr‐p‐aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15. 2 In conscious rabbits, cFP (5 mg kg−1, i.v.) markedly slowed the degradation of [3H]‐bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10–1000 ng kg−1), and inhibited the pressor response to right atrial angiotensin I (10–100 ng kg−1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg−1h−1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone. 3 In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg−1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 μg kg−1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg−1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril. 4 CFP displaced the binding of [125I]‐351A (the p‐hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 μm respectively), and inhibited rat plasma ACE activity (KI = 2.4 μm). Addition of phosphoramidon (10 μm), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems. 5 Taken together these findings suggest that the actions of cFP in vivo are attributable to inhibition of ACE rather than EP 24.15. Given that cFP is a poor inhibitor of ACE in the presence of phosphoramidon in vitro, it is likely that cFP is cleaved by a phosphoramidon‐sensitive metallopeptidase in vivo to liberate N‐[1‐(R,S)‐carboxy‐3‐phenylpropyl]‐Ala‐Ala, a potent ACE inhibitor. 1995 British Pharmacological Society

Original languageEnglish
Pages (from-to)1185-1192
Number of pages8
JournalBritish Journal of Pharmacology
Volume114
Issue number6
DOIs
Publication statusPublished - 1995
Externally publishedYes

Keywords

  • Angiotensin converting enzyme
  • blood‐pressure‐physiology
  • bradykinin
  • metalloendopeptidase 24.15

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