PT - JOURNAL ARTICLE AU - Annie Michaud AU - Tracy A. Williams AU - Marie-Thérèse Chauvet AU - Pierre Corvol TI - Substrate Dependence of Angiotensin I-Converting Enzyme Inhibition: Captopril Displays a Partial Selectivity for Inhibition of<em>N</em>-Acetyl-Seryl-Aspartyl-Lysyl-Proline Hydrolysis Compared with That of Angiotensin I<sup>·</sup> AID - 10.1124/mol.51.6.1070 DP - 1997 Jun 01 TA - Molecular Pharmacology PG - 1070--1076 VI - 51 IP - 6 4099 - http://molpharm.aspetjournals.org/content/51/6/1070.short 4100 - http://molpharm.aspetjournals.org/content/51/6/1070.full SO - Mol Pharmacol1997 Jun 01; 51 AB - Angiotensin I-converting enzyme (ACE) is composed of two highly similar domains (referred to here as the N and C domains) that play a central role in blood pressure regulation; ACE inhibitors are widely used in the treatment of hypertension. However, the negative regulator of hematopoiesis, N-acetyl-seryl-aspartyl-lysyl-prolyl (AcSDKP), is a specific substrate of the N domain-active site; thus, in addition to the cardiovascular function of ACE, the enzyme may be involved in hematopoietic stem cell regulation, raising the interest of designing N domain-specific ACE inhibitors. We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, withK i values in the subnanomolar range. However, of the inhibitors tested, captopril is the only compound able to differentiate to some degree between AcSDKP and angiotensin I inhibition of hydrolysis by wild-type ACE: theK i value with AcSDKP as substrate was 16-fold lower than that with angiotensin I as substrate. This raises the possibility of using captopril to enhance plasma AcSDKP levels with the aim of normal hematopoeitic stem cell protection during chemotherapy and a limited effect on the cardiovascular function of ACE.