SUBSTRATE DEPENDENCE OF ANGIOTENSIN I-CONVERTING ENZYME-INHIBITION - CAPTOPRIL DISPLAYS A PARTIAL SELECTIVITY FOR INHIBITION OF N-ACETYL-SERYL-ASPARTYL-LYSYL-PROLINE HYDROLYSIS COMPARED WITH THAT OF ANGIOTENSIN-I

Angiotensin I-converting enzyme (ACE) is composed of two highly simila r domains (referred to here as the N and C domains) that play a centra l role in blood pressure regulation; ACE inhibitors are widely used in the treatment of hypertension. However, the negative regulator of hem atopoiesis, N-acetyl-seryl-aspartyl-lysyl-prolyl (AcSDKP), is a specif ic substrate of the N domain-active site; thus, in addition to the car diovascular function of ACE, the enzyme may be involved in hematopoiet ic stem cell regulation, raising the interest of designing N domain-sp ecific ACE inhibitors. We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates b y wild-type ACE and the N and C domains by using a range of specific A CE inhibitors. We demonstrate that captopril, lisinopril, and fosinopr ilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K-i values in the subnanomolar range, However, of the inhibitors test ed, captopril is the only compound able to differentiate to some degre e between AcSDKP and angiotensin I inhibition of hydrolysis by wild-ty pe ACE: the K-i value with AcSDKP as substrate was 16-fold lower than that with angiotensin I as substrate. This raises the possibility of u sing captopril to enhance plasma AcSDKP levels with the aim of normal hematopoeitic stem cell protection during chemotherapy and a limited e ffect on the cardiovascular function of ACE.