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Kinins IV pp 419-425 | Cite as

Slow Tight Binding Inhibitors of Angiotensin Converting Enzyme

  • James W. Ryan
  • Alfred Y. K. Chung
  • Pierre Berryer
  • Marjoire A. Murray
  • James P. A. Ryan
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 198A)

Summary

We have found that apparent Ki values of some, but not all, carboxyalkyl-dipeptide inhibitors of angiotensin converting enzyme decrease as a function of incubation time. The most potent of the ACE inhibitors tested so far is RAC-X-65 (N-[1(S)-carboxy-3-carboxanilidiopropyl]-L-Ala-L-Pro). When RAC-X-65 is not preincubated with human serum ACE (2.4 × 10−11 M), the apparent Ki value is 4.4 × 10−10 M. Preincubation of RAC-X-65 with ACE for 15 min before addition of substrate yields an apparent Ki of 4.1 × 10−11 M. a 90 min preincubation of the inhibitor with ACE yields an apparent Ki of 1.2 × 10−11 M, i. e., the reaction of the inhibitor with enzyme is virtually stoichiometric. The enzyme:inhibitor complex is poorly separated by molecular sieve chromatography or by dilution. That such tightly bound complexes are formed in vivo is suggested by the following results: The intravenous ED50 (anesthetized rats) of RAC-X-65 is 9.43 nmol/kg, and the time for half recovery (t MATHTYPE) of responsiveness to i. v. angiotensin I, 120 ng/kg, following a cumulative dose of 240 nmol/kg of the inhibitor is 165 min. For comparison, the i. v. ED50 of captopril is 105 nmol/kg, and its t MATHTYPE following a cumulative dose of 240 nmol/kg is 16 min. Implied is the possibility that slow tight binding inhibitors of ACE may be used in a 1 pill per day regimen for the treatment of hypertension.

Keywords

Cumulative Dose Blood Pressure Response Inhibitor Complex Chlorhexidine Gluconate Monoethyl Ester 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

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Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • James W. Ryan
    • 1
  • Alfred Y. K. Chung
    • 1
  • Pierre Berryer
    • 1
  • Marjoire A. Murray
    • 1
  • James P. A. Ryan
    • 1
  1. 1.Department of MedicineUniversity of MiamiMiamiUSA

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