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

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 (K_D = 1.2 and 0.14 μm respectively), and inhibited rat plasma ACE activity (K_I = 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