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-', i.v.) markedly slowed the degradation of [3H]-bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10-1000 ng kg-' ), 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-'h -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-', i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 jig kg-') a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg-') 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 ['25I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD= 1.2 and 0.14 p M respectively), and inhibited rat plasma ACE activity (K1 = 2.4 jM). Addition of phosphoramidon (10 jLM), 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.
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