RXP 407, a selective inhibitor of the N-domain of angiotensin I-converting enzyme, blocks in vivo the degradation of hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro with no effect on angiotensin I hydrolysis.

The phosphinic peptide RXP 407 has recently been identified as the first potent selective inhibitor of the N-active site (domain) of angiotensin-converting enzyme (ACE) in vitro. The aim of this study was to probe the in vivo efficacy of this new ACE inhibitor and to assess its effect on the metabolism of AcSDKP and angiotensin I. In mice infused with increasing doses of RXP 407 (0.1--30 mg/kg/30 min), plasma concentrations of AcSDKP, a physiological substrate of the N-domain, increased significantly and dose dependently toward a plateau 4 to 6 times the basal levels. RXP 407 significantly and dose dependently inhibited ex vivo plasma ACE N-domain activity, whereas it had no inhibitory activity toward the ACE C-domain. RXP 407 (10 mg/kg) did not inhibit the pressor response to an i.v. angiotensin I bolus injection in mice. In contrast, lisinopril infusion (5 and 10 mg/kg/30 min) affected the metabolism of both AcSDKP and angiotensin I. Thus, RXP 407 is the first ACE inhibitor that might be used to control selectively AcSDKP metabolism with no effect on blood pressure regulation.