RXP 407, a selective inhibitor of the N-domain of angiotensin I-convertingenzyme, blocks in vivo the degradation of hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro with no effect on angiotensin I hydrolysis
C. Junot et al., RXP 407, a selective inhibitor of the N-domain of angiotensin I-convertingenzyme, blocks in vivo the degradation of hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro with no effect on angiotensin I hydrolysis, J PHARM EXP, 297(2), 2001, pp. 606-611
Citations number
24
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
The phosphinic peptide RXP 407 has recently been identified as the first po
tent selective inhibitor of the N-active site (domain) of angiotensin-conve
rting 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 metabol
ism of AcSDKP and angiotensin I. In mice infused with increasing doses of R
XP 407 (0.1-30 mg/kg/30 min), plasma concentrations of AcSDKP, a physiologi
cal 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.