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Vol. 297, Issue 2, 606-611, May 2001

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

Christophe Junot, Marie-Francoise Gonzales, Eric Ezan, Joel Cotton, Gilles Vazeux, Annie Michaud, Michel Azizi, Stamatia Vassiliou, Athanasios Yiotakis, Pierre Corvol and Vincent Dive

Commissariat à l'Energie Atomique, Service de Pharmacologie et d'Immunologie, Gif-sur-Yvette, France (C.J., E.E.); Institut National de la Santé et de la Recherche Médicale Unit 367, Paris, France (M.F.G.); Commissariat à l'Energie Atomique, Département d'Ingénierie et d'Etude des Protéines, Gif-sur-Yvette, France (J.C., G.V., V.D.); Institut National de la Santé et de la Recherche Médicale Unit 36, Collège de France, Paris, France (A.M., P.C.); Centre d'Investigations Cliniques 9201, Assistance Publique des Hôpitaux de Paris/Institut National de la Santé et de la Recherche Médicale, Hôpital Broussais, Paris, France (M.A.); and Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistiomiopolis, Zografou, Athens, Greece (S.V., A.Y.)

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.

0022-3565/01/2972-0606$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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