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Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor
Author(s) -
Telford Sarah E.,
Smith A. Ian,
Lew Rebecca A.,
Perich Rose B.,
Madden Anna C.,
Evans Roger G.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb13332.x
Subject(s) - captopril , bradykinin , lisinopril , chemistry , angiotensin converting enzyme , endocrinology , medicine , neprilysin , enzyme inhibitor , thiorphan , ace inhibitor , enkephalinase , phosphoramidon , angiotensin ii , pharmacology , enalaprilat , renin–angiotensin system , enzyme , blood pressure , biochemistry , receptor , enkephalin , opioid
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 [ 3 H]‐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 −1 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 −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 [ 125 I]‐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 μ m respectively), and inhibited rat plasma ACE activity ( K I = 2.4 μ m ). Addition of phosphoramidon (10 μ m ), 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.