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Research ArticleArticle

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·

Annie Michaud, Tracy A. Williams, Marie-Thérèse Chauvet and Pierre Corvol
Molecular Pharmacology June 1997, 51 (6) 1070-1076; DOI: https://doi.org/10.1124/mol.51.6.1070
Annie Michaud
Institut National de la Santé et de la Recherche Médicale Unité 36, Collège de France, 75005 Paris, France
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Tracy A. Williams
Institut National de la Santé et de la Recherche Médicale Unité 36, Collège de France, 75005 Paris, France
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Marie-Thérèse Chauvet
Institut National de la Santé et de la Recherche Médicale Unité 36, Collège de France, 75005 Paris, France
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Pierre Corvol
Institut National de la Santé et de la Recherche Médicale Unité 36, Collège de France, 75005 Paris, France
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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, 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.

Footnotes

    • Received November 8, 1996.
    • Accepted March 3, 1997.
  • 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

  • This work was supported in part by a grant from Bristol-Myers Squibb (Princeton, NJ).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 51 (6)
Molecular Pharmacology
Vol. 51, Issue 6
1 Jun 1997
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Research ArticleArticle

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·

Annie Michaud, Tracy A. Williams, Marie-Thérèse Chauvet and Pierre Corvol
Molecular Pharmacology June 1, 1997, 51 (6) 1070-1076; DOI: https://doi.org/10.1124/mol.51.6.1070

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Research ArticleArticle

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·

Annie Michaud, Tracy A. Williams, Marie-Thérèse Chauvet and Pierre Corvol
Molecular Pharmacology June 1, 1997, 51 (6) 1070-1076; DOI: https://doi.org/10.1124/mol.51.6.1070
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