Slow Tight Binding Inhibitors of Angiotensin Converting Enzyme
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.
KeywordsCumulative Dose Blood Pressure Response Inhibitor Complex Chlorhexidine Gluconate Monoethyl Ester
Unable to display preview. Download preview PDF.
- 1.J. W. Ryan, Angiotensin I converting enzyme (kininase II) peptidyl-dipeptide hydrolase EC 22.214.171.124, in: “Methods of Enzymatic Analysis,” H. U. Bergmeyer, ed., Verlag Chemie GmbH, Weinheim, Germany, Vol. 5 (1984).Google Scholar
- 3.D. H. Rich and E. T. O. Sun, Mechanism of inhibition of pepsin by pepstatin, Biochem. Pharmacol., 29: 2205–2212 (1980).Google Scholar
- 5.J. W. Ryan and U. S. Ryan, Endothelial surface enzymes and the dynamic processing of plasma substrates, Int. Rev. Pathol., 26: 1–43 (1984).Google Scholar