Substrate Dependence of Angiotensin I-Converting Enzyme Inhibition: Captopril Displays a Partial Selectivity for Inhibition ofN-Acetyl-Seryl-Aspartyl-Lysyl-Proline Hydrolysis Compared with That of Angiotensin I·
- Institut National de la Santé et de la Recherche Médicale Unité 36, Collège de France, 75005 Paris, France
Abstract
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, withKi 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: theKi 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.
Footnotes
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Send reprint requests to: Dr. Pierre Corvol, INSERM Unité 36, Collège de France, 3 rue D’Ulm, 75005 Paris, France. E-mail: corvol{at}infobiogen.fr
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↵1 M. Azizi, personal communication.
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This work was supported in part by a grant from Bristol-Myers Squibb (Princeton, NJ).
- Abbreviations:
- ACE
- angiotensin I-converting enzyme
- Ang I
- angiotensin I
- Ang II
- angiotensin II
- AcSDKP
- N-acetyl-seryl-aspartyl-lysyl-prolyl
- Hip
- hippuryl-(benzoyl-glycyl)
- HPLC
- high performance liquid chromatography
- CHO
- Chinese hamster ovary
- BSA
- bovine serum albumin
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- N domain
- amino-terminal extracellular part of the protein
- C domain
- carboxyl-terminal extracellular part of the protein
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- Received November 8, 1996.
- Accepted March 3, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
